Piperidine/piperazine derivatives

ABSTRACT

The invention further relates to a DGAT inhibitor of formula 
                         
including any stereochemically isomeric form thereof, wherein A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents —NR x —C(═O)—; —Z—C(═O)—; —Z—NR x —C(═O)—; —S(═O)p-; —C(═S)—; —NR x —C(═S)—; —Z—C(═S)—; —Z—NR x —C(═S)—; —O—C(═O)—; —C(═O)—C(═O)—; R 1  represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted; R 2  represents R 3 ; R 3  represents C 3-6 cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C 3-6 cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 
     The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/456,054, filed Aug. 11, 2014, currently pending, which is adivisional of U.S. patent application Ser. No. 12/663,009, filed Dec. 4,2009, granted as U.S. Pat. No. 8,835,437, which is the US national stageof Application No. PCT/EP2008/056983, filed Jun. 5, 2008, whichapplication claims priority from EP 07109865.1, filed Jun. 8, 2007.

FIELD OF THE INVENTION

The present invention relates to the use of a DGAT inhibitor, inparticular a DGAT1 inhibitor, for the manufacture of a medicament forthe prevention or the treatment of a disease by elevating the levels ofone or more satiety hormones, in particular GLP-1. The present inventionalso concerns piperidine/piperazine derivatives having DGAT inhibitoryactivity, in particular DGAT1 inhibitory activity. The invention furtherrelates to methods for their preparation and pharmaceutical compositionscomprising them. The invention also relates to the use of said compoundsfor the manufacture of a medicament for the prevention or the treatmentof a disease mediated by DGAT, in particular DGAT 1.

BACKGROUND TO THE INVENTION

Triglycerides represent the major form of energy stored in eukaryotes.Disorders or imbalances in triglyceride metabolism are implicated in thepathogenesis of and increased risk for obesity, insulin resistancesyndrome and type II diabetes, nonalcoholic fatty liver disease andcoronary heart disease (see, Lewis, et al, Endocrine Reviews (2002)23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:11 1).Additionally, hypertriglyceridemia is often an adverse consequence ofcancer therapy (see, Bast, et al. Cancer Medicine, 5th Ed., (2000) B. C.Decker, Hamilton, Ontario, Calif.).

A key enzyme in the synthesis of triglycerides is acylCoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal enzymethat is widely expressed in mammalian tissues and that catalyzes thejoining of 1,2-diacylglycerol (DAG) and fatty acyl CoA to formtriglycerides (TG) at the endoplasmic reticulum (reviewed in Chen andFarese, Trends Cardiovasc. Med. (2000) 10: 188 and Farese, et al, Curr.Opin. Lipidol. (2000) 11:229). It was originally thought that DGATuniquely controlled the catalysis of the final step of acylation ofdiacylglycerol to triglyceride in the two major pathways fortriglyceride synthesis, the glycerol phosphate and monoacylglycerolpathways. Because triglycerides are considered essential for survival,and their synthesis was thought to occur through a single mechanism,inhibition of triglyceride synthesis through inhibiting the activity ofDGAT has been largely unexplored.

Genes encoding mouse DGAT1 and the related human homologs ARGP1 (humanDGAT1) and ARGP2 (human ACAT2) now have been cloned and characterized(Cases, et al, Pro.c Nat.l Acad. Sci. (1998) 95:13018; Oelkers, et al,J. Biol. Chem. (1998) 273:26765). The gene for mouse DGAT1 has been usedto create DGAT knock-out mice to better elucidate the function of theDGAT gene.

Unexpectedly, mice unable to express a functional DGAT1 enzyme (Dgat1−/−mice) are viable and still able to synthesize triglycerides, indicatingthat multiple catalytic mechanisms contribute to triglyceride synthesis(Smith, et al, Nature Genetics (2000) 25:87). Other enzymes thatcatalyze triglyceride synthesis, for example, DGAT2 and diacylglyceroltransacylase, also have been identified (Cases, et al, J. Biol. Chem.(2001) 276:38870). Gene knockout studies in mice have revealed thatDGAT2 plays a fundamental role in mammalian triglyceride synthesis andis required for survival. DGAT2 deficient mice are lipopenic and diesoon after birth, apparently from profound reductions in substrates forenergy metabolism and from impaired permeability barrier function in theskin. (Farese, et al., J. Biol. Chem. (2004) 279: 11767).

Significantly, Dgat1−/− mice are resistant to diet-induced obesity andremain lean. Even when fed a high fat diet (21% fat) Dgat1−/− micemaintain weights comparable to mice fed a regular diet (4% fat) and havelower total body triglyceride levels. The obesity resistance in Dgat1−/−mice is not due to decreased caloric intake, but the result of increasedenergy expenditure and decreased resistance to insulin and leptin(Smith, et al, Nature Genetics (2000) 25:87; Chen and Farese, TrendsCardiovasc. Med. (2000) 10: 188; and Chen, et al, J. Clin. Invest.(2002) 109:1049). Additionally, Dgat1−/− mice have reduced rates oftriglyceride absorption (Buhman, et al, J. Biol. Chem. (2002)277:25474). In addition to improved triglyceride metabolism, Dgat1−/−mice also have improved glucose metabolism, with lower glucose andinsulin levels following a glucose load, in comparison to wild-type mice(Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).

The finding that multiple enzymes contribute to catalyzing the synthesisof triglyceride from diacylglycerol is significant, because it presentsthe opportunity to modulate one catalytic mechanism of this biochemicalreaction to achieve therapeutic results in an individual with minimaladverse side effects. Compounds that inhibit the conversion ofdiacylglycerol to triglyceride, for instance by specifically inhibitingthe activity of DGAT1, will find use in lowering corporealconcentrations and absorption of triglycerides to therapeuticallycounteract the pathogenic effects caused by abnormal metabolism oftriglycerides in obesity, insulin resistance syndrome and overt type IIdiabetes, congestive heart failure and atherosclerosis, and as aconsequence of cancer therapy.

Because of the ever increasing prevalence of obesity, type II diabetes,heart disease and cancer in societies throughout the world, there is apressing need in developing new therapies to effectively treat andprevent these diseases. Therefore there is an interest in developingcompounds that can potently and specifically inhibit the catalyticactivity of DGAT, in particular DGAT1.

We have now unexpectedly found that the compounds of the presentinvention exhibit DGAT inhibitory activity, in particular DGAT1inhibitory activity, and can therefore be used to prevent or treat adisease associated with or mediated by DGAT, such as for exampleobesity, type II diabetes, heart disease and cancer. The compounds ofthe invention differ from the prior art compounds in structure, in theirpharmacological activity, pharmacological potency, and/orpharmacological profile.

We have also unexpectedly found that DGAT inhibitors can be used toelevate the levels of one or more satiety hormones, in particularglucagon-like-peptide-1 (GLP-1) and therefore DGAT inhibitors, inparticular DGAT1 inhibitors, can also be used to prevent or treat adisease which can benefit from elevated levels of a satiety hormone, inparticular GLP-1. Glucagon-like peptide 1 (GLP-1) is an intestinalhormone which generally stimulates insulin secretion duringhyperglycemia, suppresses glucagon secretion, stimulates (pro) insulinbiosynthesis and decelerates gastric emptying and acid secretion. GLP-1is secreted from L cells in the small and large bowel following theingestion of fat and proteins. GLP-1 has been suggested, among otherindications, as a possible therapeutic agent for the management of type2 non-insulin-dependent diabetes mellitus as well as related metabolicdisorders, such as obesity.

Thus, by the present finding, a disease which can benefit from elevatedlevels of GLP-1 can be treated with small molecules (compared to largemolecules such as proteins or protein-like compounds, e.g. GLP-1analogues).

BACKGROUND PRIOR ART

WO 2006/034441 discloses heterocyclic derivatives and their use asstearoyl CoA desaturase inhibitors (SCD-1 inhibitors).

WO 2006/086445 relates to a combination therapy of a SCD-1 inhibitor andanother drug to treat adverse weight gain.

WO 2006/004200 and JP2007131584 relate to urea and amino derivativeshaving DGAT inhibitory activity.

WO 2004/047755 relates to fused bicyclic nitrogen-containingheterocycles having DGAT inhibitory activity.

WO2005/072740 relates to an anorectic action of a compound having DGATinhibitory activity.

DESCRIPTION OF THE INVENTION

The present invention relates to the use of a DGAT inhibitor for themanufacture of a medicament for the prevention or the treatment, inparticular for the treatment, of a disease which can benefit fromelevated levels of one or more satiety hormones, in particular GLP-1.

The present invention further relates to a compound of formula

-   including any stereochemically isomeric form thereof, wherein-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-;    —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; —O—C(═O)—;    —C(═O)—C(═O)—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆ alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;    or a 5-membered heterocycle containing at least 2 heteroatoms fused    with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein    each of said heterocycles may optionally be substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)-aminocarbonyl;    C₁₋₆alkylcarbonyl; amino; mono- or di(C₁₋₆alkyl)amino;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkyl-C₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;    Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—;-   R² represents R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle    containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,    naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may    optionally be substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently selected from hydroxyl; carboxyl; halo;    C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆ cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;    aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄    alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl-   p represents 1 or 2;-   provided that the following compounds

X R¹ R²

are excluded;a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.

The invention also relates to a compound of formula (I) as describedabove, provided that the following compounds

X R¹ R² Salt

trifluoroacetate salt

are excluded.

The present invention further relates to the use of a compound offormula (I′″) for the manufacture of a medicament for the prevention orthe treatment of a disease mediated by DGAT, in particular the presentinvention relates to the use of a compound of formula (I′″) for themanufacture of a medicament for the prevention or the treatment of adisease which can benefit from inhibition of DGAT, in particular for thetreatment of a disease which can benefit from inhibition of DGAT, inparticular DGAT1, wherein the compound of formula (I′) is a compound offormula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-;    —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; —O—C(═O)—;    —C(═O)—C(═O)—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms;

a 6-membered aromatic monocyclic heterocycle; or a 5-memberedheterocycle containing at least 2 heteroatoms fused with phenyl,cyclohexyl or a 5- or 6-membered heterocycle; wherein each of saidheterocycles may optionally be substituted with at least onesubstituent, in particular one, two, three, four or five substituents,each substituent independently being selected from hydroxyl; oxo;carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl,C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionallysubstituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)-aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono- ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkyl-C₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—;

-   R² represents R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle    containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,    naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may    optionally be substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently selected from hydroxyl; carboxyl; halo;    C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;    aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl; aryl represents phenyl or phenyl substituted with at least    one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl-   p represents 1 or 2;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

The present invention also relates to the use of a compound of formula(I) or (I′″) for the manufacture of a medicament for the prevention orthe treatment of a disease which can benefit from elevated levels of oneor more satiety hormones, in particular GLP-1, in particular the presentinvention relates to the use of a compound of formula (I) for themanufacture of a medicament for the treatment of a disease which canbenefit from elevated levels of GLP-1.

The present invention further relates to the use of a compound offormula (I) for the manufacture of a medicament for the prevention orthe treatment of a disease mediated by DGAT, in particular the presentinvention relates to the use of a compound of formula (I) for themanufacture of a medicament for the prevention or the treatment of adisease which can benefit from inhibition of DGAT, in particular for thetreatment of a disease which can benefit from inhibition of DGAT, inparticular DGAT1.

As used hereinbefore or hereinafter C₀₋₃alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 0 (then it represents a direct bond) to 3 carbon atoms suchas methyl, ethyl, propyl, 1-methylethyl; C₁₋₂alkyl as a group or part ofa group defines straight or branched chain saturated hydrocarbonradicals having 1 or 2 carbon atoms such as methyl, ethyl; C₁₋₄alkyl asa group or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as methyl,ethyl, propyl, 1-methylethyl, butyl; C₁₋₅alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 5 carbon atoms such as the group defined for C₁₋₄alkyland pentyl, 2-methylbutyl and the like; C₁₋₆alkyl as a group or part ofa group defines straight or branched chain saturated hydrocarbonradicals having from 1 to 6 carbon atoms such as the group defined forC₁₋₄alkyl and for C₁₋₅alkyl and hexyl, 2-methylpentyl and the like;C₁₋₆alkanediyl defines straight or branched chain saturated bivalenthydrocarbon radicals having from 1 to 6 carbon atoms such as methylene,1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene,1,4-butanediyl or 1,4-butylidene, 1,5-pentanediyl and the like; C₂₋₆alkenyl as a group or part of a group defines straight or branched chainhydrocarbon radicals having from 2 to 6 carbon atoms and having a doublebond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl,3-methylbutenyl and the like; C₂₋₆alkenediyl defines straight orbranched chain bivalent hydrocarbon radicals having from 2 to 6 carbonatoms and having a double bond such as 1,2-ethenediyl, 1,3-propenediyl,1,4-butenediyl, 1,5-pentenediyl and the like; C₂₋₆alkynediyl as a groupor part of a group defines straight or branched chain bivalenthydrocarbon radicals having from 2 to 6 carbon atoms and having a triplebond such as 1,2-ethynediyl, 1,3-propynediyl, 1,4-butynediyl,1,5-pentynediyl and the like; C₃₋₆cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term halo is generic to fluoro, chloro, bromo and iodo. As usedhereinbefore or hereinafter, polyhaloC₁₋₆alkyl as a group or part of agroup is defined as C₁₋₆alkyl substituted with one or more, such as forexample 2, 3, 4 or 5 halo atoms, for example methyl substituted with oneor more fluoro atoms, for example, difluoromethyl or trifluoromethyl,1,1-difluoro-ethyl, 1,1-difluoro-2,2,2-trifluoro-ethyl and the like. Incase more than one halogen atoms are attached to a C₁₋₆alkyl groupwithin the definition of polyhaloC₁₋₆alkyl, they may be the same ordifferent.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom. Oxo means ═O.

The radical R¹ as defined hereinabove may be an optionally substituted5-membered monocyclic heterocycle containing at least 2 heteroatoms, anoptionally substituted 6-membered aromatic monocyclic heterocycle or anoptionally substituted 5-membered heterocycle containing at least 2heteroatoms fused with a phenyl, cyclohexyl or a 5- or 6-memberedheterocycle.

A 5-membered monocyclic heterocycle as defined hereinabove orhereinafter may be a 5-membered monocyclic non-aromatic (fully saturatedor partially saturated) or aromatic heterocycle containing at least 2heteroatom, in particular 2 or 3 heteroatoms, each independentlyselected from O, S, S(═O)_(p) or N. Examples of such unsubstitutedmonocyclic 5-membered heterocycles comprise, but are not limited to,non-aromatic (fully saturated or partially saturated) or aromatic5-membered monocyclic heterocycles such as for example 1,3-dioxolanyl,imidazolidinyl, thiazolidinyl, dihydrooxazolyl, isothiazolidinyl,isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl,pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl and the like. Optional substituents of the aboveheterocycles are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with carboxyl, C₁₋₄alkyloxy-carbonyl or aryl-C(═O)—;hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono- or di(C₁₋₄alkyl)-aminocarbonyl; C₁₋₆alkylcarbonyl;amino; mono- or di(C₁₋₆alkyl)amino;

R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

A 6-membered aromatic monocyclic heterocycle as defined hereinabove orhereinafter contains at least one heteroatom, in particular 1, 2 or 3heteroatoms, each independently selected from O, S, S(═O)_(p) or N.Examples of such unsubstituted monocyclic 6-membered aromaticheterocycles comprise, but are not limited to, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like. Optionalsubstituents of the above heterocycles are hydroxyl; oxo; carboxyl;halo; C₁₋₆alkyl optionally substituted with carboxyl,C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionallysubstituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono- ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

A 5-membered heterocycle containing at least 2 heteroatoms fused withphenyl, cyclohexyl or a 5- or 6-membered heterocycle as definedhereinabove or hereinafter may be a non-aromatic (fully saturated orpartially saturated) or aromatic 5-membered heterocycle containing atleast 2 heteroatoms, in particular 2 or 3 heteroatoms, eachindependently selected from O, S, S(═O)_(p) or N, in particular O, S orN, more in particular O or N, fused with phenyl, cyclohexyl or a 5- or6-membered non-aromatic (fully saturated or partially saturated) oraromatic heterocycle containing at least one heteroatom, in particular1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p)or N. Examples of such unsubstituted bicyclic heterocycles comprise, butare not limited to, non-aromatic (fully saturated or partiallysaturated) or aromatic 8- or 9-membered bicyclic heterocycles such asfor example 1,3-benzodioxolyl, benzoxazolyl, benzimidazolyl, indazolyl,benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl,benzothiadiazolyl, benzotriazolyl, purinyl, pyrrolopyridyl,thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl,isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl,pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl,thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl,pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl,thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl,pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl,thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl,thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl,pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl,thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl,thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl,thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl,thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl,imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl,isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl,oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl,oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl and thelike. Optional substituents of the above heterocycles are hydroxyl; oxo;carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl,C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionallysubstituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆ alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono- ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

The radical Het as defined hereinabove may be an optionally substitutedmonocyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom selected from O, S, S(═O)_(p) or N; or a optionallysubstituted bi- or tricyclic non-aromatic or aromatic heterocyclecontaining at least one heteroatom selected from O, S, S(═O)_(p) or N.Examples of such unsubstituted monocyclic heterocycles comprise, but arenot limited to, non-aromatic (fully saturated or partially saturated) oraromatic 4-, 5-, 6- or 7-membered monocyclic heterocycles such as forexample azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, pyrrolinyl, imidazolinyl, pyrazolinyl,pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl,tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,pyranyl and the like. Examples of such unsubstituted bicyclic ortricyclic heterocycles comprise, but are not limited to, non-aromatic(fully saturated or partially saturated) or aromatic 8- to 17-memberedbicyclic or tricyclic heterocycles such as for exampledecahydroquinolinyl, octahydroindolyl, 2,3-dihydrobenzofuranyl,1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl,isobenzofuryl, benzothienyl, isobenzothienyl, indolizinyl, indolyl,isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, imidazopyrazolyl; isoxazolotriazinyl,isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl,thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl,thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl and the like. Optionalsubstituents of the above heterocycles are hydroxyl; oxo; carboxyl;halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino or mono-or di-(C₁₋₄ alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl.

Examples of a 6-membered aromatic heterocycle containing 1 or 2 N atomsin the definition of R³ are pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl.

When any variable occurs more than one time in any constituent (e.g.aryl, Het), each definition is independent.

The term Het or R¹ is meant to include all the possible isomeric formsof the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and2H-pyrrolyl.

The carbocycles or heterocycles covered by the terms aryl, Het, R¹ or R³may be attached to the remainder of the molecule of formula (I) throughany ring carbon or heteroatom as appropriate, if not otherwisespecified. Thus, for example, when the heterocycle is imidazolyl, it maybe 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when thecarbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl andthe like.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

When X is defined as for instance —NR^(x)—C(═O)—, this means that thenitrogen of NR″ is linked to the R² substituent and the carbon atom ofC(═O) is linked to the nitrogen of the ring

Thus the left part of the bivalent radical in the definition of X islinked to the R² substituent and the right part of the bivalent radicalin the definition of X is linked to the ring moiety

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, suchas for example for R⁴ and R⁵, all possible combinations are intendedwhich are chemically possible.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable salts as mentioned hereinbefore orhereinafter are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic,2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely the salt form can be converted by treatment withalkali into the free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases. Thepharmaceutically acceptable salts as mentioned hereinbefore orhereinafter are meant to also comprise the therapeutically activenon-toxic metal or amine addition salt forms (base addition salt forms)which the compounds of formula (I) are able to form. Appropriate baseaddition salt forms comprise, for example, the ammonium salts, thealkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like.

Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term salt also comprises the quaternary ammonium salts (quaternaryamines) which the compounds of formula (I) are able to form by reactionbetween a basic nitrogen of a compound of formula (I) and an appropriatequaternizing agent, such as, for example, an optionally substitutedC₁₋₆alkylhalide, arylhalide, C₁₋₆alkyl-carbonylhalide,arylcarbonylhalide, or arylC₁₋₆alkylhalide, e.g. methyliodide orbenzyliodide. Other reactants with good leaving groups may also be used,such as for example C₁₋₆alkyl trifluoromethanesulfonates, C₁₋₆alkylmethanesulfonates, and C₁₋₆alkyl p-toluenesulfonates. A quaternary aminehas a positively charged nitrogen. Pharmaceutically acceptablecounterions include chloro, bromo, iodo, trifluoroacetate, acetate,triflate, sulfate, sulfonate. The counterion of choice can be introducedusing ion exchange resins.

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of formula (I) are able to form, as well as salts thereof.Examples of such forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, salts, and solvates may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore orhereinafter defines all the possible stereoisomeric forms which thecompounds of formula (I), and their N-oxides, salts, or solvates maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure as wellas each of the individual isomeric forms of formula (I) and theirN-oxides, salts or solvates, substantially free, i.e. associated withless than 10%, preferably less than 5%, in particular less than 2% andmost preferably less than 1% of the other isomers. Thus, when a compoundof formula (I) is for instance specified as (E), this means that thecompound is substantially free of the (Z) isomer.

In particular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E (entgegen) or Z (zusammen)-stereochemistry at saiddouble bond. The terms cis, trans, R, S, E and Z are well known to aperson skilled in the art.

Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

Following CAS-nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where the first R* is alwaysspecified as the reference center and [R*,R*] indicates centers with thesame chirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system relative to the position of the highest prioritysubstituent on the reference atom is denominated “α”, if it is on thesame side of the mean plane determined by the ring system, or “β”, if itis on the other side of the mean plane determined by the ring system.

The compounds of (I) may be synthesized in the form of racemic mixturesof enantiomers which can be separated from one another followingart-known resolution procedures. The racemic compounds of formula (I)may be converted into the corresponding diastereomeric salt forms byreaction with a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Whenever used hereinafter, the term “compounds of formula (I)” or anysubgroup thereof, is meant to also include their N-oxide forms, theirsalts, their stereochemically isomeric forms and their solvates. Ofspecial interest are those compounds of formula (I) which arestereochemically pure.

A first embodiment of the present invention are those compounds offormula (I) having the following formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-;    —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;    or a 5-membered heterocycle containing at least 2 heteroatoms fused    with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein    each of said heterocycles may optionally be substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-Me-; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R² represents R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said    C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl may optionally be substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl;-   p represents 1 or 2;-   provided that the following compounds

X R¹ R²

are excluded;a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.

The invention also relates to a compound of formula (I) as described inthe above embodiment, provided that the following compounds

X R¹ R² Salt

trifluoroacetate salt

are excluded.

A second embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein X represents —NR^(x)—C(═O)—;—Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-; —NR^(x)—C(═S)— or —O—C(═O)—; inparticular X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—;more in particular X represents —NR^(x)—C(═O)— or —Z—C(═O)—.

A third embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein A represents N.

A fourth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein A represents CH, in particularwherein A represents CH and the dotted line does not represent a bond.

A fifth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein R¹ represents a 5-membered monocyclicheterocycle containing at least 2 heteroatoms, in particular pyrazolyl,triazolyl or oxadiazolyl; a 6-membered monocyclic aromatic heterocycle,in particular pyrimidinyl; or a 5-membered aromatic heterocyclecontaining at least 2 heteroatoms fused with a 5-membered heterocycle,in particular imidazopyrazolyl or imidazothiazolyl; wherein each of saidheterocycles may optionally be substituted, preferably with one or twosubstituents. Particular substituents of said heterocycles include oxo,C₁₋₆alkyl optionally substituted with aryl-C(═O)— orC₁₋₄alkyloxycarbonyl; hydroxyC₁₋₆alkyl optionally substituted with arylor aryl-C(═O)—; amino; mono- or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—; more inparticular C₁₋₆alkyl optionally substituted with aryl-C(═O)— orC₁₋₄alkyloxycarbonyl; hydroxyC₁₋₆alkyl optionally substituted with aryl;mono- or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;Het-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; aryl; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl orHet.

A sixth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein the compound of formula (I) is acompound of formula (I′)

wherein R^(3a) and R^(3a) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted withhydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;cyano; aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—; Het-O—.

A seventh embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein the compound of formula (I) is acompound of formula (I″)

wherein R^(3a) and R^(3a) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3′) representshydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substitutedwith hydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substitutedwith C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substitutedwith aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—.

An eighth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein the compound of formula (I) is acompound of formula (I′) or (I″) and wherein R^(3a) and R^(3b) eachindependently represent halo, polyhaloC₁₋₆alkyl, C₁₋₆alkyl orC₁₋₆alkyloxy, in particular both R^(3a) and R^(3b) represent halo, morein particular both R^(3a) and R^(3b) represent chloro.

A ninth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein the compound of formula (I) is acompound of formula (I′) or (I″) and wherein R^(3′) represents hydrogen,hydroxyl, carboxyl; halo; amino; mono- or di-(C₁₋₄ alkyl)amino;C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylthio;C₁₋₄alkylcarbonylamino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; Het-C(═O)— orHetC₁₋₄alkyl; or R^(3c) represents hydrogen.

A tenth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein p represents 2.

An eleventh embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein Z represents C₁₋₆alkanediyl, inparticular CH₂ or CH₂—CH₂.

A twelfth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein R^(x) represents hydrogen.

A thirteenth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein R⁸ represents hydrogen.

A fourteenth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein R⁸ represents halo, C₁₋₄alkyl orC₁₋₄alkyl substituted with hydroxyl; in particular R⁸ represents halo orC₁₋₄alkyl.

A fifteenth embodiment of the present invention are those compounds offormula (I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment wherein R³ represents C₃₋₆cycloalkyl, phenyl,naphtalenyl, 1,3-benzodioxolyl or a 6-membered aromatic heterocyclecontaining 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,naphtalenyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle mayoptionally be substituted with at least one substituent, in particularone or two substituents, preferably each substituent independentlyselected from hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substitutedwith hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkyloxycarbonyl; amino; mono- or di(C₁₋₄alkyl)amino;C₁₋₄alkylcarbonylamino; Het; HetC₁₋₄alkyl.

A sixteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein one or more, preferably all, of the followingrestrictions apply:

-   a) X represents —NR^(x)—C(═O)—; or —Z—C(═O)—;-   b) the compound of formula (I) is a compound of formula (I″), in    particular a compound of formula (I″) wherein R^(3a) and R^(3b)    represent halo; more in particular chloro; and wherein R^(3c)    represents hydrogen;-   c) A represents N;-   d) A represents CH;-   e) the dotted line does not represent a bond;-   f) Z represents C₁₋₆alkanediyl;-   g) R¹ represents a 5-membered monocyclic aromatic heterocycle    containing at least 2 heteroatoms, in particular pyrazolyl or    triazolyl; a 6-membered monocyclic aromatic heterocycle; or a    5-membered aromatic heterocycle containing at least 2 heteroatoms    fused with a 5-membered heterocycle; each of said heterocycles    optionally being substituted, in particular substituted with oxo,    C₁₋₆alkyl optionally substituted with aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl; C₃₋₆cycloalkyl-NR^(x)—;    Het-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; aryl; arylC₁₋₄alkyl.-   h) R^(x) represents hydrogen.

A seventeenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein one or more, preferably all, of the followingrestrictions apply:

-   a) A represents CH or N;-   b) the dotted line does not represents a bond in case A represents a    carbon atom;-   c) X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—;-   d) Z represents a bivalent radical selected from C₁₋₆alkanediyl;-   e) R^(x) represents hydrogen;-   f) R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;    or a 5-membered heterocycle containing at least 2 heteroatoms fused    with a 5-membered heterocycle; wherein each of said heterocycles    such as for example pyrazolyl, triazolyl, oxadiazolyl, pyrimidinyl,    imidazopyrazolyl or imidazothienyl, may optionally be substituted    with at least one substituent, in particular one or two    substituents, each substituent independently being selected from    oxo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxycarbonyl;    hydroxyC₁₋₆alkyl optionally substituted with aryl; mono- or    di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; Het-NR^(x)—;    arylC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    aryl; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; Het;-   g) R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    1,3-benzodioxolyl, or a 6-membered aromatic heterocycle containing 1    or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl, naphtalenyl,    1,3-benzodioxolyl or 6-membered aromatic heterocycle may optionally    be substituted with at least one substituent, in particular one or    two substituents, each substituent independently selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; Het; HetC₁₋₄alkyl;-   h) R⁴ represents hydrogen or C₁₋₄alkyl;-   i) R⁵ represents hydrogen or C₁₋₄alkyl;-   j) R⁸ represents hydrogen;-   k) aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one substituent, said substituent being    selected from halo; C₁₋₆alkyl; C₁₋₆alkyloxy;-   l) Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle optionally being substituted with    C₁₋₆alkyloxycarbonyl.

Preferred compounds of formula (I) are selected from

A X R¹ R^(q) N

H— N

H— N

H— N

N

N

HOCH₂—a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.

In general, compounds of formula (I) wherein X represents X₁—NH—C(═O)—with X₁ representing a direct bond or Z, said compounds beingrepresented by formula (I-a), can be prepared by reacting anintermediate of formula (II) with an intermediate of formula (III) inthe presence of a suitable solvent, such as for exampleN,N-dimethylformamide or dichloromethane or acetonitrile, optionally inthe presence of a suitable base, such as for exampleN,N-diethyl-ethanamine Intermediates of formula (II) are commerciallyavailable or can be prepared by reacting R²—X₁—NH₂ with phosgene in thepresence of a suitable solvent, such as for example toluene.

The above reaction can also be performed as a fast synthesis reactionthereby using appropriate reagents well-known for fast synthesis, suchas for example for the purification of the reaction mixture1-ethenyl-4-(isocyanatomethyl)-benzene polymer with ethenylbenzene andtris-2-aminoethylamine linked to polystyrene can be used.

Compounds of formula (I-a) wherein X₁ represents a direct bond, saidcompounds being represented by formula (I-a-1), can be prepared byreacting an intermediate of formula (II′) with Cl₃COC(═O)—Cl orC(═O)Cl₂, optionally in the presence of HCl in diethylether, and in thepresence of a suitable solvent, such as for example toluene oracetonitrile, followed by reaction with an intermediate of formula (III)in the presence of a suitable solvent, such as for example acetonitrile,

N,N-dimethylformamide or dichloromethane, optionally in the presence ofa suitable base, such as for example N,N-diethyl-ethanamine orN,N-diisopropyl-ethanamine

Compounds of formula (I) wherein X represents —X₁—C(═O)— with X₁representing a direct bond or Z, said compounds being represented byformula (I-b), can be prepared by reacting an intermediate of formula(IV) with an intermediate of formula (III) in the presence of a suitabledehydrating (coupling) agent, such as for exampleN′-(ethyl-carbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methyl-amino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,tetrahydrofuran or dichloromethane, and optionally in the presence of asuitable base, such as for example N,N-diisopropyl-ethanamine orN,N-diethyl-ethanamine. This reaction of an intermediate of formula (IV)with an intermediate of formula (III) can also be performed in thepresence of a suitable activating agent, such as for exampleCl—C(═O)—C(═O)—Cl, a suitable base, such as for exampleN,N-diethyl-ethanamine, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I-b) wherein X₁ represents a direct bond, saidcompounds being represented by formula (I-b-1), can be prepared byreacting an intermediate of formula (IV′) wherein W₁ represents asuitable leaving group, such as for example halo, e.g. chloro and thelike, with an intermediate of formula (III) in the presence of asuitable base, such as for example N-methyl morpholine, and a suitablesolvent, such as for example N,N-dimethylformamide.

Compounds of formula (I) wherein X represents X₁—NH—C(═S)— with X₁representing a direct bond or Z, said compounds being represented byformula (I-c), can be prepared by reacting an intermediate of formula(XV) with an intermediate of formula (III) in the presence of a suitablesolvent, such as for example tetrahydrofuran or dichloromethane,optionally in the presence of a suitable base, such as for exampleN,N-diethyl-ethanamine

Compounds of formula (I) wherein X represents —S(═O)_(p)—, saidcompounds being represented by formula (I-d), can be prepared byreacting an intermediate of formula (XIV) wherein W₃ represents asuitable leaving group, such as for example halo, e.g. chloro and thelike, with an intermediate of formula (III) in the presence of asuitable base, such as for example N,N-diisopropyl-ethanamine orN,N-diethyl-ethanamine, and a suitable solvent, such as for exampledichloromethane.

Compounds of formula (I) wherein X represents —C(═O)—C₂₋₆alkenediyl-,said compounds being represented by formula (I-e), can be prepared byreacting an intermediate of formula (XV) with an intermediate of formula(III) in the presence of a suitable solvent, such as for example analcohol, e.g. ethanol.

Compounds of formula (I) wherein R² represents R³, said R³ beingsubstituted with R⁵R⁴N—C₁₋₆alkyl, said R² being represented by—R^(3′)—C₁₋₆alkyl-NR⁴R⁵ and said compounds being represented by formula(I-f), can be prepared by reacting an intermediate of formula (XVI)wherein W₄ represents a suitable leaving group, such as for exampleCH₃—S(═O)₂—O—, with NHR⁴R⁵ in the presence of a suitable solvent, suchas for example acetonitrile. Intermediates of formula (XVI) can beprepared by reacting the corresponding OH derivatives with CH₃—S(═O)₂—Clin the presence of a suitable base, such as for example pyridine, and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein the R¹ substituent is substituted withamino can be prepared from the corresponding compound wherein the aminofunction is protected by a suitable protecting group, such as forexample a tertiair butyloxycarbonyl group, in the presence of a suitableacid, such as for example trifluoroacetic acid, and a suitable solvent,such as for example dichloromethane. Said protected compounds can beprepared according to the synthesis protocol described hereinabove.

Compounds of formula (I) wherein X contains Z, said Z being substitutedwith amino, said X being represented by Z¹(NH₂)—X₂, wherein X₂represents the remainder of the linker X, and said compounds beingrepresented by formula (I-g), can be prepared by deprotecting anintermediate of formula (XVIII) wherein P represents a suitable leavinggroup, such as for example tert butoxycarbonyl, with a suitable acid,such as for example trifluoroacetic acid, in the presence of a suitablesolvent, such as for example dichloromethane

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein R¹ or R² is unsubstituted, can beconverted into a compound wherein R¹ or R² contain aC₁₋₄alkyl-S(═O)_(p)— substituent, by reaction withC₁₋₄alkyl-S(═O)_(p)—W₅ wherein W₅ represents a suitable leaving group,such as for example halo, e.g. chloro and the like, in the presence of asuitable base, such as for example N,N-diethyl-ethanamine, and in thepresence of a suitable solvent, such as for example acetonitrile.

Compounds of formula (I) wherein R¹ or R² contains aC₁₋₆alkyloxycarbonyl substituent, can be converted into a compound offormula (I) wherein R¹ or R² contain a carboxyl substituent, by reactionwith a suitable base, such as for example sodium hydroxide, in thepresence of a suitable solvent, such as for example dioxane.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₆alkyloxycarbonylsubstituent, can also be converted into a compound of formula (I)wherein R¹ or R² contain a CH₂—OH substituent, by reaction with asuitable reducing agent, such as for example LiBH, in the presence of asuitable solvent, such as for example tetrahydrofuran or dioxane.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₆alkyloxycarbonylsubstituent, can also be converted into a compound of formula (I)wherein R¹ or R² are unsubstituted by reaction with a suitable acid,such as for example hydrochloric acid and the like.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₅alkyl-carbonylsubstituent, can be converted into a compound of formula (I) wherein R¹or R² contain a C₁₋₅alkyl-CH(OH)— substituent, by reaction with asuitable reducing agent, such as for example NaBH₄, in the presence of asuitable solvent, such as for example an alcohol, e.g. methanol.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₆alkyloxysubstituent, can be converted into a compound of formula (I) wherein R¹or R² contain a OH substituent, by reaction with a suitable reducingagent, such as for example BBr₃, in the presence of a suitable solvent,such as for example dichloromethane or dichloroethane.

Compounds of formula (I) wherein R¹ or R² contain a carboxylsubstituent, can be converted into a compound of formula (I) wherein R¹or R² contain a Het-C(═O)— substituent wherein Het represents anoptionally substituted monocyclic saturated heterocycle containing atleast one N atom, said heterocycle being linked via the N atom to theC(═O) group, by reaction with said heterocycle in the presence asuitable dehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)-methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. This reaction canalso be performed as a fast synthesis reaction thereby using appropriatereagents well-known for fast synthesis, such as for exampledicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI), linked toan appropriate carrier, e.g. polystyrene. Also for the purification ofthe reaction mixture, appropriate fast-synthesis reagents can be used,such as for example 1-ethenyl-4-(isocyanatomethyl)-benzene polymer withethenylbenzene.

The compounds of formula (I) and some of the intermediates in thepresent invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, chiral liquid chromatography and the like methods.Enantiomers can be obtained from racemic mixtures by first convertingsaid racemic mixtures with suitable resolving agents such as, forexample, chiral acids, to mixtures of diastereomeric salts or compounds;then physically separating said mixtures of diastereomeric salts orcompounds by, for example, selective crystallization or chromatographictechniques, e.g. liquid chromatography and the like methods; and finallyconverting said separated diastereomeric salts or compounds into thecorresponding enantiomers. Pure stereochemically isomeric forms may alsobe obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography or SCF (Super Critical Fluid) chromatography, inparticular using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (III) can be prepared by deprotecting anintermediate of formula (V) wherein P represents a suitable protectivegroup, such as for example benzyl or C₁₋₄alkyloxycarbonyl, e.g.CH₃CH₂—O—C(═O)— or (CH₃)₃C—O—C(═O)—.

In the above reaction, when P represents for instance benzyl,appropriate deprotection conditions are deprotection in the presence ofH₂, a suitable catalyst, such as for example palladium on charcoal orPd(OH)₂, a suitable solvent, such as for example tetrahydrofuran or analcohol, e.g. methanol. When P represents for instance (CH₃)₃C—O—C(═O)—,appropriate deprotection conditions are deprotection in the presence ofa suitable acid, such as for example HCl or trifluoroacetic acid, in thepresence of a suitable solvent, such as for example acetonitrile,dichloromethane or an alcohol, e.g. propanol. When P represents forinstance CH₃CH₂—O—C(═O)—, appropriate deprotection conditions aredeprotection in the presence of a suitable acid, such as for exampleHBr, in the presence of Na₂SO₃, or deprotection in the presence of asuitable base, such as for example KOH, in the presence of a suitablesolvent, such as for example water, ethylene glycol or an alcohol, e.g.propanol.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted pyrazolyl, said intermediates being represented by formula(V-a) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (VI) with anintermediate of formula (VII) in the presence of a suitable solvent,such as for example an alcohol, e.g. ethanol, and optionally in thepresence of sodium.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted triazolyl, said intermediates being represented by formula(V-b) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (VIII) with anintermediate of formula (VII) in the presence of a suitable solvent,such as for example an alcohol, e.g. ethanol, and in the presence of asuitable base, such as for example sodium, or in the presence of asuitable acid, such as for example acetic acid.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted pyrimidinyl, said intermediates being represented by formula(V-c) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (VI) with anintermediate of formula (IX) in the presence of a suitable solvent, suchas for example an alcohol, e.g. ethanol, and optionally in the presenceof sodium.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted imidazopyrazolyl, said intermediates being represented byformula (V-d) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (X) with an intermediateof formula (XI) in the presence of a suitable solvent, such as forexample N,N-dimethylformamide, a suitable base, such as for exampleDIPEA, and a suitable dehydrating (coupling) agent, such as for exampleN-(ethyl-carbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methyl-amino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, followed byreaction with POCl₃ in the presence of a suitable solvent, such as forexample dioxane. This reaction of an intermediate of formula (X) with anintermediate of formula (XI) can also be performed in the presence of asuitable activating agent, such as for example Cl—C(═O)—C(═O)—Cl, asuitable base, such as for example N,N-diethyl-ethanamine, and asuitable solvent, such as for example N,N-dimethylformamide.Alternatively, intermediates of formula (V-d) can also be directlyprepared from an intermediate of formula (X) and an intermediate offormula (XI) in the presence of POCl₃.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted oxadiazole, said intermediates being represented by formula(V-e-1) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (X) with an intermediateof formula (XXI) in the presence of a suitable solvent, such as forexample N,N-dimethylformamide, a suitable base, such as for exampleDIPEA, and a suitable dehydrating (coupling) agent, such as for exampleN-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride(EDCI), dicyclohexylcarbodiimide (DCC), carbonyl diimidazole (CDI),1-[bis(di-methyl-amino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, followed byreaction of the resulting intermediate of formula (XXII) with Burgess'reagent (CAS 29684-56-8) in the presence of a suitable solvent, such asfor example tetrahydrofuran.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted oxadiazole, said intermediates being represented by formula(V-e-2) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (XXIII) with anintermediate of formula (XXIV) in the presence of a suitable base, suchas for example sodium hydride, and a suitable solvent, such as forexample tetrahydrofuran.

Intermediates of formula (V) wherein R¹ represents optionallysubstituted imidazothiazole, said intermediates being represented byformula (V-f) wherein R^(1a) represents the optional substituent, can beprepared by reacting an intermediate of formula (XII) (see below) withBr₂ in the presence of HBr/acetic acid, followed by reacting theresulting intermediate of formula (XXV) with 2-amino-thiazole in thepresence of a suitable solvent, such as for example an alcohol, e.g.ethanol.

When R¹ in an intermediate of formula (V) represents an unsubstitutedheterocycle or triazolone an appropriate substituent R^(1a) can beintroduced by reaction with W₁—R^(1a), wherein W₁ represents a suitableleaving group, such as for example halo, e.g. chloro or bromo, in thepresence of a suitable base, such as for example NaH, KOH, Na₂CO₃ orCs₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide.

Intermediates of formula (X) wherein P is for instance benzyl can beprepared by hydrolysis of the corresponding ester in the presence of asuitable acid, such as for example HCl, or a suitable base, such as forexample sodium hydroxide, in the presence of a suitable solvent, such asfor example dioxane. Or intermediates of formula (X) wherein P is(CH₃)₃C—O—C(═O)— can be prepared by hydrolysis of the correspondingester in the presence of a suitable base, such as for example sodiumhydroxide, and a suitable solvent, such as for example tetrahydrofuran,dioxane or an alcohol, e.g. methanol. The corresponding esters can beprepared by reacting the protected piperidine/piperazine with ethylbenzoate substituted in position 4 with a suitable leaving group, suchas for example halo, e.g. fluoro and the like, in a suitable solvent,such as for example N,N-dimethylacetamide.

Intermediates of formula (VI) can be prepared by reacting anintermediate of formula (XII) with CH₃O—CH(OCH₃)—N(CH₃)₂.

Intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (XIII) with CH₃O—CH(OCH₃)—N(CH₃)₂.

Intermediates of formula (XII) wherein P represents tertiairbutyloxycarbonyl, can be prepared by reacting1-[4-(1-piperazinyl)phenyl]ethanone with C,C′-bis(1,1-dimethylethyl)dicarbonic acid ester in the presence of a suitable solvent, such as forexample dichloromethane. Intermediates of formula (XII) wherein Prepresents benzyl can be prepare by reacting1-[4-(1-piperazinyl)phenyl]ethanone with benzylbromide in the presenceof a suitable base, such as for example Na₂CO₃, and a suitable solvent,such as for example tetrahydrofuran.

Intermediates of formula (XIII) can be prepared by reacting anintermediate of formula (X) with NH₃ in the presence of a suitablesolvent, such as for example N,N-dimethylformamide, and in the presenceof a suitable dehydrating (coupling) agent, such as for exampleN-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride(EDCI), dicyclohexylcarbodiimide (DCC), carbonyl diimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole.

Intermediates of formula (II) wherein X₁ represents a direct bond and R²contains a Het-C₁₋₄alkyl substituent, wherein Het represents amonocyclic, saturated N containing heterocycle represented by formula(XXXII), said intermediate of formula (IV) being represented by formula(II-a), can be prepared by reacting an intermediate of formula (XXI)with an intermediate of formula (XXVI) in the represence of a suitabledehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethylamino)-methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. The resultingintermediate of formula (XXVII) can then be reduced in a next step inthe presence of a suitable reducing agent, such as for example borane,in the presence of a suitable solvent, such as for exampletetrahydrofuran, to an intermediate of formula (XXVIII), which can thenbe converted into an intermediate of formula (II-a) with phosgene in thepresence of HCl in diethylether and a suitable solvent, such as forexample toluene or acetonitrile. Intermediates of formula (XXVII) canalso be converted into an intermediate of formula (II-b) with phosgenein the presence of HCl in diethylether and a suitable solvent, such asfor example toluene or acetonitrile or dichloromethane.

Intermediates of formula (II′) wherein R² contains a Het-C₁₋₄alkylsubstituent, said intermediate being represented by formula (II′-a), canbe prepared by reacting an intermediate of formula (XIX) with anintermediate of formula (XX) wherein W₆ represents a suitable leavinggroup, such as for example halo, e.g. chloro and the like, in thepresence of a suitable solvent, such as for example acetonitrile,resulting in an intermediate of formula (II′-a) with can be convertedinto an intermediate of formula (II-a) as described hereinabove forintermediate (XXVIII).

Intermediates of formula (IV) can be prepared by hydrolysis of anintermediate of formula (XXIX)) in the presence of LiOH, an acid, suchas for example HCl, and a suitable solvent, such as for example analcohol, e.g. methanol. Intermediates of formula (XXIX)) wherein R²contains Het-C₁₋₄alkyl as substituent, said intermediates beingrepresented by formula (XXIX-a) can be prepared by reacting anintermediate of formula (XXX) wherein W₇ represents a suitable leavinggroup, such as for example halo, e.g. bromo and the like, with anintermediate of formula (XXI). Intermediates of formula (XXX-a) asdepicted below, can be prepared by reacting an intermediate of formula(XXXI) with N-bromosuccinimide in the presence of2,2′-(1,2-diazenediyl)-bis[2-methylpropanenitrile] and a suitablesolvent, such as for example CCl₄.

Intermediates of formula (XXXI) wherein X₁ represents CH₂, saidintermediates being represented by formula (XXXI-a), can be prepared byreacting an intermediate of formula (XXXII) with sodium metal, in thepresence of a suitable alcohol of formula C₁₋₄alkyl-OH, followed byadding a suitable acid, such as for example sulfuric acid. Intermediatesof formula (XXXII) can be prepared by reacting an intermediate offormula (II′-b) with 1,1-dimethylethyl-nitrous acid ester, CuCl₂,1,1-dichloroethene in a suitable solvent, such as for exampleacetonitrile.

Intermediates of formula (XXVIII-a) can be prepared by reacting anintermediate of formula (IV) wherein X₁ is substituted with a protected(P, such as for example tertiair butyloxycarbonyl) amino group, saidintermediate being represented by formula (IV-a), with an intermediateof formula (III) in the presence of a suitable dehydrating (coupling)agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)-methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine.

Intermediates of formula (IV) wherein X₁ represents CHOH, saidintermediates being represented by formula (IV-b) can be prepared byreducing an intermediate of formula (XVII) in the presence of ZnBr₂,Si(CH₃)₃—CN and an acid, such as for example HCl, in the presence of asuitable solvent, such as for example dichloromethane. Intermediates offormula (XVII) can be prepared by reacting an intermediate of formula(XXXIII) wherein W₈ represents a suitable leaving group, such as forexample halo, e.g. bromo and the like, with N,N-dimethylformamide in thepresence of BuLi and a suitable solvent, such as for exampletetrahydrofuran.

Pharmacological Part

As already indicated above, the present invention relates to the use ofa DGAT inhibitor, in particular a DGAT1 inhibitor, to elevate levels ofone or more satiety hormones, in particular GLP-1 levels. The presentinvention also relates to the use of a DGAT inhibitor, in particular aDGAT1 inhibitor, for the manufacture of a medicament for the preventionor the treatment, in particular for the treatment, of a disease whichcan benefit from an elevated level of one or more satiety hormones, inparticular a disease which can benefit from an elevated GLP-1 level. Inparticular, GLP-1 levels are elevated in plasma or in portal blood, morein particular in plasma. By elevated GLP-1 levels, e.g. elevated GLP-1plasma level or an elevated GLP-1 level in portal blood, it is meantthat the GLP-1 level of a subject having taken a DGAT1 inhibitor iselevated or increased compared to the subject under the same conditionsbut not having taken the DGAT1 inhibitor. In particular GLP-1 levels areelevated in fasting conditions or postprandial, more in particularpostprandial.

Therapeutic uses for a compound which elevates GLP-1 level include, butare not limited to, improving learning, enhancing neuro-protection,and/or alleviating a symptom of a disease or disorder of the centralnervous system, e.g., through modulation of neurogenesis, and e.g.,Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS,stroke, hemorrhage, cerebrovascular accident, ADD, and neuropsychiatricsyndromes; converting liver stem/progenitor cells into functionalpancreatic cells; preventing beta-cell deterioration and stimulation ofbeta-cell proliferation; treating pancreatitis; treating obesity;suppressing appetite and inducing satiety; treating irritable bowelsyndrome or inflammatory bowel disease such as Crohn's disease andulcerative colitis; reducing the morbidity and/or mortality associatedwith myocardial infarction and stroke; treating acute coronary syndromecharacterized by an absence of Q-wave myocardial infarction; attenuatingpost-surgical catabolic changes; treating hibernating myocardium ordiabetic cardiomyopathy; suppressing plasma blood levels ofnorepinepherine; increasing urinary sodium excretion, decreasing urinarypotassium concentration; treating conditions or disorders associatedwith toxic hypervolemia, e.g., renal failure, congestive heart failure,nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension;inducing an inotropic response and increasing cardiac contractility;treating polycystic ovary syndrome; treating respiratory distress;improving nutrition via a non-alimentary route, i.e., via intravenous,subcutaneous, intramuscular, peritoneal, or other injection or infusion;treating nephropathy; treating left ventricular systolic dysfunction,e.g., with abnormal left ventricular ejection fraction; inhibitingantro-duodenal motility, e.g., for the treatment or prevention ofgastrointestinal disorders such as diarrhea, postoperative dumpingsyndrome and irritable bowel syndrome, and as premedication inendoscopic procedures; treating critical illness polyneuropathy (CIPN)and systemic inflammatory response syndrome (SIRS); modulatingtriglyceride levels and treating dyslipidemia; treating organ tissueinjury (e.g. brain tissue injury) caused by reperfusion of blood flowfollowing ischemia; improving the function of ischemic and reperfusedbrain tissue; treating coronary heart disease risk factor (CHDRF)syndrome. Further diseases which can benefit from an elevated GLP-1level, include, but are not limited to, ischemic myocardial stunning;ishemic/reperfusion injury; acute myocardial infarction; leftventricular dysfunction; vascular disease; neuropathy, includingperiphere sensoric neuropathy associated with type II diabetes;bone-related disorders, including osteoporosis, obesity, diabetes.Because of the effect on GLP-1, the DGAT inhibitors can also be used toprovide cardioprotection.

References supporting the above indications include ExperimentalNeurology, Vol. 203(2), pp 293-301 (2007); U.S. Pat. No. 7,186,683; J.Pharm. Exp. Ther. vol. 312, No. 1, pp 303-308 (2005); Diabetes, vol. 54,pp 146-151 (2005); US2007/0021339, which are incorporated herein byreference.

In view of the DGAT inhibitory activity, in particular the DGAT1inhibitory activity, the present compounds of formula (I), their N-oxideforms, their pharmaceutically acceptable salts or their solvates, can beused as a medicine. In particular, the present invention relates to acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof for use as a medicine, inparticular for use as a medicine for the prevention or the treatment ofa disease which can benefit from an elevated GLP-1 level. In particular,the present invention also relates to the use of a compound of formula(I) for the manufacture of a medicament for the prevention or thetreatment of a disease which can benefit from an elevated GLP-1 level,such as the diseases and disorders mentioned above.

In view of the above-described utility for a DGAT inhibitor, inparticular a DGAT1 inhibitor, there is provided a method of treating awarm-blooded mammal, including a human, suffering from or a method ofpreventing a warm-blooded mammal, including a human, to suffer from adisease which can benefit from an elevated level of GLP-1, in particulara method of treating a warm-blooded mammal, including a human, sufferingfrom a disease which can benefit from an elevated level of GLP-1. Saidmethods comprise the administration of an effective amount of a DGATinhibitor, in particular a DGAT1 inhibitor, to a warm-blooded mammal,including a human.

In view of the DGAT inhibitory activity of the compounds of formula (I),there is provided a method of treating a warm-blooded mammal, includinga human, suffering from or a method of preventing a warm-blooded mammal,including a human, to suffer from a disease which can benefit from anelevated level of GLP-1, in particular a method of treating awarm-blooded mammal, including a human, suffering from a disease whichcan benefit from an elevated level of GLP-1. Said methods comprise theadministration of an effective amount of a compound of formula (I), aN-oxide form thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, to a warm-blooded mammal, including a human.

In view of the DGAT inhibitory activity, in particular the DGAT1inhibitory activity, the present invention also relates to a compound offormula (I), a N-oxide form thereof, a pharmaceutically acceptable saltthereof or a solvate thereof for use as a medicine, in particular foruse as a medicine for the prevention or the treatment of a diseaseswhich can benefit from inhibition of DGAT, in particular DGAT1. Theinvention also relates to the use of a compound of formula (I), aN-oxide form thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, for the manufacture of a medicament for the preventionor the treatment of a disease or disorder which can benefit frominhibition of DGAT, in particular DGAT1. Diseases or disorders which canbenefit from inhibition of DGAT, in particular DGAT1 include, but arenot limited to metabolic disorders, such as obesity and obesity relateddisorders (including peripheral vascular disease, cardiac failure,myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes,in particular type II diabetes mellitus, and complications arisingtherefrom (such as retinopathy, neuropathy, nephropathy), syndrome X,insulin resistance, impaired glucose tolerance, conditions of impairedfasting glucose, hypoglycemia, hyperglycemia, hyperuricemia,hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia,dyslipidemia, mixed dyslipidemia, hypertriglyceridemia and nonalcoholicfatty liver disease, fatty liver, increased mesenteric fat,non-alcoholic steatohepatitis, liverfibrosis, metabolic acidosis,ketosis, dysmetabolic syndrome; dermatological conditions such as acne,psoriasis; cardiovascular diseases, such as atherosclerosis,arteriosclerosis, acute heart failure, congestive heart failure,coronary artery disease, cardiomyopathy, myocardial infarction, anginapectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis and vascular stenosis;neoplastic diseases, such as solid tumors, skin cancer, melanoma,lymphoma and endothelial cancers, e.g., breast cancer, lung cancer,colorectal cancer, stomach cancer, other cancers of the gastrointestinaltract (e.g., esophageal cancer and pancreatic cancer), prostate cancer,kidney cancer, liver cancer, bladder cancer, cervical cancer, uterinecancer, testicular cancer and ovarian cancer; and other diseases andconditions that are sensitive or responsive to modulation, in particularinhibition, of DGAT function, in particular DGAT1 function.

Particular diseases or disorders which can benefit from inhibition ofDGAT, in particular DGAT1, are selected from obesity,hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia,hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease,liverfibrosis, non-alcoholic steatohepatitis and diabetes, in particulartype II diabetes.

In view of the DGAT inhibitory activity of the compounds of formula (I),there is provided a method of treating a warm-blooded mammal, includinga human, suffering from or a method of preventing a warm-blooded mammal,including a human, to suffer from a disease which can benefit frominhibition of DGAT, in particular a method of treating a warm-bloodedmammal, including a human, suffering from a disease which can benefitfrom inhibition of DGAT. Said methods comprise the administration of aneffective amount of a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, to awarm-blooded mammal, including a human.

The present invention also provides compositions for preventing ortreating a disease which can benefit from an elevated GLP-1 level orwhich can benefit from inhibition of DGAT, in particular DGAT1, inparticular for treating a disease which can benefit from elevated GLP-1levels or which can benefit from inhibition of DGAT, in particularDGAT1. Said compositions comprise a therapeutically effective amount ofa compound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and a pharmaceuticallyacceptable carrier.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, optionally in salt form, as the active ingredient is combinedin intimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable,particularly, for administration orally, rectally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs,emulsions and solutions; or solid carriers such as starches, sugars,kaolin, diluents, lubricants, binders, disintegrating agents and thelike in the case of powders, pills, capsules, and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit forms, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations, whichare intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

The compounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

The compounds of the present invention may also be topicallyadministered in the form of drops, in particular eye drops. Said eyedrops may be in the form of a solution or a suspension. Any systemdeveloped for the delivery of solutions or suspensions as eye drops aresuitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of formula (I), and, from 1 to 99.95% by weight,more preferably from 30 to 99.9% by weight, even more preferably from 50to 99.9% by weight of a pharmaceutically acceptable carrier, allpercentages being based on the total weight of the composition.

In view of the above described effects of DGAT inhibitors and/or theeffect on GLP-1 levels by DGAT inhibitors, the present invention alsorelates to

-   a) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and a dipeptidyl peptidase-4 inhibitor (DPP-4    inhibitor).

DPP-4 is a membrane-spanning cell surface aminopeptidase widelyexpressed in many tissues, such as liver, lung, kidney, intestinalbrush-border membranes, lymphocytes, endothelial cells. DPP-4 cleavespeptides with a proline or alanine residue in the second aminoterminalposition. Many gastro-intestinal hormones are substrates for DPP-4,among them GLP-1. A DPP-4 inhibitor thus inhibits cleavage of GLP-1 andhence provides for an increase in the level of GLP-1. Therefore, acombination as indicated above can be used to combine the activity ofthe DGAT inhibitor and the DPP4 inhibitor in order to elevate GLP-1levels. By administering a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof, with a DPP4 inhibitor, different mechanisms may be targeted inorder to achieve elevated levels of GLP-1. In this way, the use of sucha combination may reduce the dosage of the DGAT inhibitor and the DPP4inhibitor required for a desired elevation in GLP-1 level as compared towhen the DGAT inhibitor or the DPP4 inhibitor is administered as amonotherapy. Therefore, these combinations may reduce or eliminate sideeffects of monotherapy while not interfering with the GLP-1 levelincreasing activity. Also, the combination of a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and a DPP4 inhibitor can be used as a medicine.The present invention also relates to a product comprising (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) a DPP4 inhibitor,as a combined preparation for simultaneous, separate or sequential usein the treatment of a disease which can benefit from an elevated levelof GLP-1. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers. SaidDPP4 inhibitor which may be combined with a DGAT inhibitor according tothe present invention, in particular a DGAT1 inhibitor, may be a knownDPP4 inhibitor such as for example sitagliptin, vildagliptin, andsaxagliptin.

-   b) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and a GLP-1 analogue. Said GLP-1 analogue can be    considered as an agonist at the GLP-1 receptor.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and a GLP-1 analogue can be used as a medicine. The presentinvention also relates to a product containing (a) a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and (b) a GLP-1 analogue, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a disease which can benefit from an elevated level ofGLP-1. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers.

Said GLP-1 analogue which may be combined with a DGAT inhibitoraccording to the present invention may be a known GLP-1 analogue such asfor example exenatide, exenatide LAR or liraglutide.

-   c) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an anti-diabeticum.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an anti-diabeticum can be used as a medicine. The presentinvention also relates to a product containing (a) a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and (b) an anti-diabeticum, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a disease which can benefit from an elevated level of GLP-1or DGAT inhibition, such as for example diabetes, in particular type IIdiabetes. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers. Saidanti-diabeticum which may be combined with a DGAT inhibitor according tothe present invention may be a known anti-diabeticum such as for examplemetformin, glibenclamide, rosiglitazon, pioglitazon, repaglinide,glimepiride, acarbose, glicazide, glipizide, nateglinide, tolbutamide, aprotein tyrosine phosphatase 1 inhibitor, or a 11-beta-hydroxysteroiddehydrogenase inhibitor.

-   d) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and a phosphodiesterase (PDE) inhibitor, in    particular a PDE10A or PDE11A inhibitor. Phosphodiesterase (PDE)    inhibitors, in particular PDE10A or PDE11A inhibitors, are known to    be insulin secretagogues, and to enhance the signalling of GLP-1 by    inhibition of the hydrolysis of cAMP.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and a phosphodiesterase (PDE) inhibitor, in particular a PDE10Aor PDE11A inhibitor, can be used as a medicine. The present inventionalso relates to a product containing (a) a DGAT inhibitor, in particulara DGAT1 inhibitor, more in particular a compound of formula (I), aN-oxide form thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, and (b) a phosphodiesterase (PDE) inhibitor, inparticular a PDE10A or PDE11A inhibitor, as a combined preparation forsimultaneous, separate or sequential use in the treatment of a diseasewhich can benefit from an elevated level of GLP-1 or DGAT inhibition,such as for example diabetes, in particular type II diabetes, orobesity. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers. Saidphosphodiesterase (PDE) inhibitor, in particular a PDE10A or PDE11Ainhibitor, which may be combined with a DGAT inhibitor according to thepresent invention may be a known PDE inhibitor such as for examplepapaverine, PQ-10, dipyridamole, ibudilast or tadalafil.

-   e) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an appetite suppressant.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an appetite suppressant can be used as a medicine. Thepresent invention also relates to a product containing (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) an appetitesuppressant, as a combined preparation for simultaneous, separate orsequential use in the treatment of a disease which can benefit from anelevated level of GLP-1 or DGAT inhibition, such as for examplediabetes, in particular type II diabetes, or obesity. The differentdrugs of such a combination or product may be combined in a singlepreparation together with pharmaceutically acceptable carriers or theymay each be present in a separate preparation together withpharmaceutically acceptable carriers. Said appetite suppressants, whichmay be combined with a DGAT inhibitor according to the present inventionmay be a known appetite suppressant such as for example sibutramine andphentermine

-   f) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an anti-obesity drug with a CNS (central    nervous system) mode of action such as for example a CB 1 antagonist    or inverse agonists.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an anti-obesity drug with a CNS (central nervous system)mode of action can be used as a medicine. The present invention alsorelates to a product containing (a) a DGAT inhibitor, in particular aDGAT1 inhibitor, more in particular a compound of formula (I), a N-oxideform thereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and (b) an anti-obesity drug with a CNS (central nervoussystem) mode of action, as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease which canbenefit from an elevated level of GLP-1 or DGAT inhibition, such as forexample diabetes, in particular type II diabetes, or obesity. Thedifferent drugs of such a combination or product may be combined in asingle preparation together with pharmaceutically acceptable carriers orthey may each be present in a separate preparation together withpharmaceutically acceptable carriers. Said anti-obesity drugs with a CNS(central nervous system) mode of action, which may be combined with aDGAT inhibitor according to the present invention may be a known aanti-obesity drug such as for example Rimonabant, orlistat, SLV-319, orMK-0364.

-   g) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an hypolipidemic drug such as for example    3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase    inhibitors, squalene synthase inhibitors, FXR (farnesoid X receptor)    and LXR (liver X receptor) ligands, cholestyramine, fibrates,    nicotinic acid and aspirin.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an hypolipidemic drug can be used as a medicine. Thepresent invention also relates to a product containing (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) an hypolipidemicdrug, as a combined preparation for simultaneous, separate or sequentialuse in the treatment of a disease which can benefit from an elevatedlevel of GLP-1 or DGAT inhibition, such as for example diabetes, inparticular type II diabetes, or obesity. The different drugs of such acombination or product may be combined in a single preparation togetherwith pharmaceutically acceptable carriers or they may each be present ina separate preparation together with pharmaceutically acceptablecarriers. Said hypolipidemic drug which may be combined with a DGATinhibitor according to the present invention may be a knownhypolipidemic drug such as for example lovastatin, pravastatin,simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin.

-   h) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an agonist of peroxisome proliferator-activator    receptor such as for example fenofibrate.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an agonist of peroxisome proliferator-activator receptorsuch as for example fenofibrate, can be used as a medicine. The presentinvention also relates to a product containing (a) a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and (b) an agonist of peroxisomeproliferator-activator receptor such as for example fenofibrate, as acombined preparation for simultaneous, separate or sequential use in thetreatment of a disease which can benefit from an elevated level of GLP-1or DGAT inhibition, such as for example diabetes, in particular type IIdiabetes, or obesity. The different drugs of such a combination orproduct may be combined in a single preparation together withpharmaceutically acceptable carriers or they may each be present in aseparate preparation together with pharmaceutically acceptable carriers.

-   i) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an antihypertensive agent.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an antihypertensive agent, can be used as a medicine. Thepresent invention also relates to a product containing (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) anantihypertensive agent, as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease which canbenefit from an elevated level of GLP-1 or DGAT inhibition, such as forexample diabetes, in particular type II diabetes, or obesity. Thedifferent drugs of such a combination or product may be combined in asingle preparation together with pharmaceutically acceptable carriers orthey may each be present in a separate preparation together withpharmaceutically acceptable carriers. Said anti-hypertensive agent whichmay be combined with a DGAT inhibitor according to the present inventionmay be a known anti-hypertensive agent, e g loop diuretics such asethacrynic acid, furosemide and torsemide, angiotensin converting enzyme(ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na—K-ATPase membrane pump such asdigoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors suchas omapatrilat, sampatrilat and fasidotril; angiotensin II antagonistssuch as candesartan, eprosartan, irbesartan, losartan, telmisartan andvalsartan, in particular valsartan; renin inhibitors such as ditekiren,zankiren, terlakiren, aliskiren, RO 66-1132 and RO-66-1168; β-adrenergicreceptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol,metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agentssuch as digoxin, dobutamine and milrinone; calcium channel blockers suchas amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine,nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists;and aldosterone synthase inhibitors.

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter, the term ‘THF’ means tetrahydrofuran, ‘Et₂O’ means diethylether, ‘CH₃OH’ means methanol, ‘Pd(OH)₂’ means palladium hydroxide,‘POCl₃’ means phosphoric trichloride, ‘EtOAc’ means ethyl acetate,‘Na₂CO₃’ means carbonic acid disodium salt, ‘NaHCO₃’ means carbonic acidmonosodium salt, ‘CH₂Cl₂’ or ‘DCM’ means dichloromethane, ‘CH₃CN’ meansacetonitrile, ‘EtOH’ means ethanol, ‘DIPE’ means diisopropyl ether,‘HBTU’ means1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide,‘DMF’ means N,N-dimethylformamide, ‘DMA’ means N,N-dimethylacetamide,‘DIPEA’ means N-ethyl-N-(1-methylethyl)-2-propanamine, ‘HOBt’ means1-hydroxy-1H-benzotriazole, ‘Na₂SO₃’ means sulphurous acid, disodiumsalt, ‘KOH’ means potassium hydroxide, ‘iPrOH’ means 2-propanol, ‘EDCI’means N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride, ‘HCTU” means1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide.

Isolute HM-N™ filter is a product of Argonaut, Foster City, Calif.94404, USA, and is a short column comprising a modified form ofdiatomaceous earth that can remove water from a sample in combinatorialchemistry applications.

Extrelut™ is a product of Merck KgaA, Darmstadt, Germany, and is a shortcolumn comprising diatomaceous earth.

A number of compounds were purified by reversed phase high-performanceliquid chromatography using one of the methods below (indicated in thecompound procedure with method A, method B and method C). Whennecessary, these methods can be slightly adjusted by a person skilled inthe art to obtain a more optimal result for the separation.

HPLC Method A

The product was purified by reversed-phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). Two mobile phases were used (phase A: a 0.25%NH₄HCO₃ solution in water; phase B: CH₃CN). First, 85% A and 15% B witha flow rate of 40 ml/min was hold for 0.5 minutes. Then a gradient wasapplied to 10% A and 90% B in 41 minutes with a flow rate of 80 ml/min.Then a gradient was applied to 100% B in 20 minutes with a flow rate of80 ml/min and hold for 4 minutes.

HPLC Method B

The product was purified by reversed-phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). Two mobile phases were used (phase A: 90% of a0.5% NH₄OAc solution in water+10% CH₃CN; phase B: CH₃CN). First, 85% Aand 15% B with a flow rate of 40 ml/min was hold for 0.5 minutes. Then agradient was applied to 10% A and 90% B in 41 minutes with a flow rateof 80 ml/min. Then a gradient was applied to 100% B in 20 minutes with aflow rate of 80 ml/min and hold for 4 minutes.

HPLC Method C

The product was purified by reversed phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). Three mobile phases were used (phase A: 90% of a0.5% NH₄OAc solution in water+10% CH₃CN; phase B: CH₃OH; phase C:CH₃CN). First, 75% A and 25% B with a flow rate of 40 ml/min was holdfor 0.5 minutes. Then a gradient was applied to 50% B and 50% C in 41minutes with a flow rate of 80 ml/min. Then a gradient was applied to100% C in 20 minutes with a flow rate of 80 ml/min and hold for 4minutes.

A. Preparation of the Intermediates Example A1 a) Preparation ofIntermediate 1

4-[4-(Phenylmethyl)-1-piperazinyl]benzoic acid, ethyl ester (58 g) wassuspended in an aqueous HCl solution (430 ml, 2 N) and the reactionmixture was stirred for 17 hours at 100° C. Water was removed byevaporation, co-evaporated twice with dioxane, and the residue wassuspended in Et₂O and filtered, yielding 55.4 g (84%) of intermediate 1as blue solid (0.2HCl).

b) Preparation of Intermediate 2

1-[(4-Methylphenyl)methyl]-1H-pyrazole-4,5-diamine, sulfate (2:1) (1.48g, 0.005887 mol), intermediate 1 (2.5 g, 0.00677 mol), HOBt (1.08 g,0.007064 mol) and HBTU (2.68 g, 0.007064 mmol) were dissolved in DMF (22ml). DIPEA (3 ml, 0.01766 mol) was added dropwise and the reactionmixture was stirred for 3 hours. To the reaction mixture was added anaqueous Na₂CO₃ solution (170 ml, half saturated) and EtOAc (35 ml). Theformed precipitate was filtered off, washed with H₂O and EtOAc, anddried, yielding 1.93 g (68%) of intermediate 2 as pink powder.

c) Preparation of Intermediate 3

Intermediate 2 (1.9 g) was dissolved in dioxane (28 ml), and POCl₃ (28ml) was added to the solution. The reaction mixture was heated for 90minutes at 40° C., 90 minutes at 60° C. and for 2 hours at 80° C.Afterwards POCl₃ was distilled off and the residue was dissolved indioxane (2 ml) and treated with an ice cold aqueous Na₂CO₃ solution(half saturated). The organic material was extracted with EtOAc (3×),dried (Na₂SO₄), filtered and the solvent was evaporated. The residue waspurified by flash chromatography (Si 60, EtOAc/hexane gradient from 1:1to 1:0) to yield 1.3 g (73%) of intermediate 3 as a yellow powder.

d) Preparation of Intermediate 4

Intermediate 3 (0.5 g) dissolved in CH₃OH (15 ml)/THF (2 ml) washydrogenated for 17 hours in the presence of Pd(OH)₂ (0.1 g). Thereaction mixture was filtered over Celite, washed with THF/CH₃OH (1/1)and evaporated to yield 0.396 g of intermediate 4 as a yellow powder.

Example A2 a) Preparation of Intermediate 5

A mixture of 4-(4-acetylphenyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester (12.16 g, 0.04 mol) and1,1-dimethoxy-N,N-dimethylmethanamine (100 ml) was stirred and refluxedfor 48 hours at 120° C. (oil bath). Subsequently, the mixture wascooled. The precipitate was filtered off, washed with DIPE and dried,yielding 8.7 g of intermediate 5.

b) Preparation of Intermediates 6 and 7

A mixture of sodium (0.096 g, 0.004 mol) and EtOH (10 ml, p.a.) wasstirred at room temperature till a solution was obtained.(2-Phenylethyl)-hydrazine sulfate (0.468 g, 0.002 mol) was added and themixture was stirred for 20 minutes. Intermediate 5 (0.539 g, 0.0015 mol)was added and the mixture was stirred for 144 hours at 85° C. Thesolvent was evaporated. The residue was stirred in H₂O (2 ml) and theproduct was extracted with CH₂Cl₂. The mixture was dried over an Isolutefilter and the organic layer was evaporated. The residue was purified byHPLC Method A. Two different product fractions were collected and thesolvent of each fraction was evaporated, yielding intermediate 6 andintermediate 7, residues were used as such in a next reaction.

c) Preparation of Intermediate 8

A mixture of intermediate 6 (0.091 g, 0.00021 mol), HCl/2-propanol (1.5ml) and CH₃CN (3 ml) was stirred for 3 hours at room temperature. Thesolvent was evaporated (by a N₂ stream at 40° C.). The crude residue wasdried, yielding 0.085 g of intermediate 8 (0.2HCl).

Example A3 a) Preparation of Intermediate 9

A mixture of sodium (0.036 g, 0.0015 mol) in EtOH (5 ml) was stirred atroom temperature until the mixture became a solution. SubsequentlyN-cyclohexylguanidine sulfate (2:1) (0.285 g, 0.00075 mol) was added tothe solution and the mixture was stirred for 15 minutes at roomtemperature. Intermediate 5 (0.539 g, 0.0015 mol) was added and themixture was stirred for 188 hours at 85° C. The solvent was evaporatedand the residue was stirred in H₂O (2 ml). The product was extractedwith CH₂Cl₂. The mixture was filtered over an Isolute filter and thesolvent was evaporated. The residue was purified by reversed phase HPLC.The pure fractions were collected and worked-up, yielding 0.33 g ofintermediate 9, used as such in the next reaction.

b) Preparation of Intermediate 10

A mixture of intermediate 9 (0.330 g, 0.00075 mol), HCl/2-propanol (3ml) and CH₃CN (6 ml) was stirred for 3 hours at room temperature. Thesolvent was evaporated under N₂ at 40° C. and the residue was dried,yielding 0.307 of intermediate 10 (0.2HCl).

Example A4 a) Preparation of Intermediate 11

A mixture of 4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylic acid,1,1-dimethylethyl ester (6.4 g, 0.0200 mol) in THF (200 ml) and CH₃OH(50 ml) was stirred at room temperature. 1N aqueous NaOH solution (200ml, 0.200 mol) was added. The mixture was stirred for 4 hours at 50° C.1N HCl (200 ml) was added and the product was precipitated. The productwas filtered off, washed with water and dried, yielding 4.8 g ofintermediate 11.

b) Preparation of Intermediate 12

A mixture of intermediate 11 (6.7 g, 0.0220 mol),N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,monohydrochloride (4.79 g, 0.0250 mol), 1-hydroxy-1H-benzotriazole (3.38g, 0.0250 mol) and DMF was stirred at room temperature for 30 minutes.NH₃ was passed through the solution for 5 minutes (cooling with ice) andthe mixture was stirred at room temperature for 18 hours. NH₃ was passedagain for 5 minutes through the solution and the mixture was stirred for2 hours at room temperature. H₂O (50 ml) was added and the product wasprecipitated. The product was filtered off, washed with water and dried,yielding 5.77 g (85%) of intermediate 12.

c) Preparation of Intermediate 13

A mixture of intermediate 12 (1.5 g, 0.005 mol) and1,1-dimethoxy-N,N-dimethylmethanamine (20 ml) was stirred for 5 hours at120° C. The mixture was cooled. The product was precipitated, filteredoff, washed (DIPE) and dried, yielding 1.170 g (65%) of intermediate 13.

d) Preparation of Intermediate 14

A mixture of intermediate 13 (0.180 g, 0.0005 mol), butylhydrazine,ethanedioate (1:1) (0.107 g, 0.0006 mol) and HOAc (4 ml) was stirred for2 hours at 50° C. The solvent was evaporated (N₂ stream at 50° C.),yielding 0.192 g of intermediate 14 used as such in the next reactionstep.

e) Preparation of Intermediate 15

A mixture of intermediate 14 (0.192 g, 0.0005 mol), HCl/2-propanol (1.5ml) and CH₃CN (3 ml) was stirred for 3 hours at room temperature. Thesolvent was evaporated (N₂ stream at 50° C.), yielding 0.179 g ofintermediate 15 (0.2HCl) used as such in the next reaction (ExampleB2c).

Example A5 a) Preparation of Intermediate 16

A mixture of4-[4-(1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylicacid, ethyl ester (0.032 mol), 2-bromo-1-(4-bromophenyl)-1-butanone(0.04 mol) and Na₂CO₃ (0.08 mol) in DMF (150 ml) was stirred and heatedat 40° C. overnight. The mixture was filtered off and the filtrate wasevaporated. The oily residue was stirred up in CH₂Cl₂/H₂O and separated.The organic layer was dried, filtered off and evaporated till a smallvolume. The oily residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/hexane/EtOAc 1/1/1). The pure fractions werecollected and evaporated. The residue was purified again by columnchromatography over silica gel (eluent: CH₂Cl₂/EtOAc/hexane 1/1/1). Thepure fractions were collected and evaporated. The oily residue (12 g)was crystallized from Et₂O, yielding 9 g (52%) of intermediate 16.

b) Preparation of Intermediate 17

A mixture of Na₂SO₃ (1 g) in a 48% HBr solution (250 ml) was stirred for10 minutes. Intermediate 16 (0.062 mol) was added. The mixture wasstirred and refluxed for 5 hours. The mixture was stirred at roomtemperature overnight. The solvent was evaporated, yielding 21 g (72%)of intermediate 17 (.HBr).

Example A6 a) Preparation of Intermediate 18

A mixture of4-[4-(1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylicacid, ethyl ester (0.0063 mol), (1-chloroethyl)benzene (0.0063 mol) andKOH (0.0063 mol) in DMF (30 ml) was stirred and heated overnight at 70°C., then the reaction mixture was cooled and poured out into ice/H₂O.The resulting precipitate was filtered off and washed with water. Thesolids were recrystallised from EtOAc/hexane and the pure product wascollected, yielding 1 g (38%) of intermediate 18.

b) Preparation of Intermediate 19

A mixture of intermediate 18 (6.08 g, 0.0150 mol) and NaHSO₃ (0.78 g,0.0075 mol) in HBr (5 ml; 48%) was stirred and refluxed for 48 hours.Then the solvent was evaporated. The residue was washed with an alkalineaqueous solution. The aqueous layer was extracted with CH₂Cl₂ and theseparated organic layer was dried, filtered and the solvent wasevaporated. The crude residue was purified by column chromatography(eluent: first EtOAc and then CH₃OH (yielding intermediate 19)). Theproduct fractions were collected and the solvent was evaporated. Yield:1.5 g of intermediate 19 (29%; m.p.: 178-180° C.).

Example A7 a) Preparation of Intermediate 20

Reaction under N₂ atmosphere. A solution of4-(4-aminophenyl)-1-piperidine-carboxylic acid, 1,1-dimethylethyl ester(0.39 mol) in 1-methyl-2-pyrrolidinone (210 ml) was stirred and heatedto 140° C. [(Dimethylamino)methylene]hydrazine-carboxylic acid, ethylester (0.465 mol) was added in four portions, each portion added after20 minutes. The reaction mixture was stirred for 3 hours at 140° C. Themixture was allowed to cool to room temperature. H₂O (800 ml) was addedand the resulting precipitate was filtered off and dried (vacuum, 50°C., 24 hours, under a gentle stream of N₂), yielding 134 g (100%) ofintermediate 20.

b) Preparation of Intermediate 21

A mixture of intermediate 20 (0.27 mol), 2-bromopropane (0.78 mol) andCs₂CO₃ (0.39 mol) in DMA (580 ml) was stirred for 5 hours at 50° C.,then overnight at room temperature. The mixture was poured out intowater (1500 ml). CH₂Cl₂ (1 L) was added. The layers were separated. Theorganic layer was washed with water (5×1.0 L), dried (MgSO₄), filteredand the solvent was evaporated. The residue was stirred in 2-propanoland the resulting precipitate was filtered off and dried (vacuum, 50°C.), yielding 72.8 g of intermediate 21.

c) Preparation of Intermediate 22

A mixture of intermediate 21 (199 g, 0.51 mol) in CH₂Cl₂ (800 ml, c.p.(chemical pure)) was stirred at room temperature. HCl (1.18 mol, c.p.)was added and the reaction mixture was heated slowly to 40° C. Thereaction mixture was stirred overnight at 40° C. HCl (50 ml, c.p.) wasadded and the mixture was stirred for 4 hours at 40° C., then allowed tocool to room temperature. The layers were separated. The water layer wasalkalized (until pH=10). The resulting precipitate was filtered off,dissolved in CH₂Cl₂ and the organic solution was dried (MgSO₄), filteredand the solvent was evaporated. The residue was stirred in EtOAc,filtered off and dried (vacuum, 50° C.), yielding 103 g (70%) ofintermediate 22.

Example A8 a) Preparation of Intermediate 23

1-(1-Methylethyl)-1H-pyrazole-4,5-diamine, sulfate (2:1) (46 g, 0.1928mol), intermediate 1 (89 g, 0.241 mol),6-chloro-1-hydroxy-1H-benzotriazole (3.3 g, 0.01928 mol) and HCTU (95.7g, 0.2314 mol) were dissolved in DMF (530 ml). To the reaction mixturewas added DIPEA (165 ml, 0.964 mol) within 5 minutes and the mixture wasstirred for 17 hours at room temperature. To the reaction mixture wasadded an aqueous Na₂CO₃ (half saturated) solution and the organicmaterial was extracted with EtOAc, dried (Na₂SO₄), filtered and thesolvent was evaporated. The crude was suspended in Et₂O and filtered,yielding 60.4 g (75%) of intermediate 23 as pink powder.

b) Preparation of Intermediate 24

Intermediate 23 (30 g) was dissolved in dioxane (250 ml). POCl₃ (250 ml)was added to the solution. The reaction mixture was heated for 1 hour at40° C. and subsequently dioxane (100 ml) was added and heating wascontinued for 2 hours at 80° C. Afterwards POCl₃ was distilled off andthe residue was dissolved in dioxane (100 ml) and treated with an icecold aqueous Na₂CO₃ (half saturated) solution. The organic material wasextracted with EtOAc (3×), dried (Na₂SO₄), filtered and the solvent wasevaporated. The residue was purified by flash chromatography (Si 60,EtOAc). The most clean fractions were suspended in Et₂O and filtered,yielding 16.88 g (59%) of intermediate 24 as a brown powder.

c) Preparation of Intermediate 25

Intermediate 24 (16.8 g) was dissolved in CH₃OH (330 ml). The solutionwas hydrogenated for 6 hours in the presence of Pd(OH)₂ (8.4 g). Afterfiltration over Celite, the solvent was evaporated, yielding 13.28 g ofintermediate 25 as a yellow powder.

Example A9 a) Preparation of Intermediate 26

(+−)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-(1-piperazinyl)phenyl]-3H-1,2,4-triazol-3-onedihydrochloride.monohydrate (0.0087 mol) in CH₃OH (100 ml) andCH₃OH/NH₄OH (10 ml) was cooled till −20° C. and the mixture waswarmed-up slowly to room temperature. The mixture was poured into H₂Oand the solid was filtered off. The precipitate was crystallized from2-propanol. The product was dried in vacuo for 24 hours at 100° C.Yield: 2.9 g of intermediate 26 (78%).

Example A 10 a) Preparation of Intermediate 27

A solution of ethyl 4-fluorobenzoic acid ester (17.51 g; 0.104 mol) and1-benzyl-piperazine (36.83 g; 0.209 mol) in DMA (100 ml) was stirred andrefluxed for 15 hours. The reaction mixture was allowed to reach roomtemperature and poured into ±750 ml stirring H₂O. The solid part wasfiltered off, washed with plenty of water, dried for 15 hours at 50° C.in vacuo, recrystallized with 150 ml iPrOH, filtered off, washed withiPrOH and dried for 48 hours at 50° C. in vacuo, yielding 27.11 g ofintermediate 27 (80%).

b) Preparation of Intermediate 28

Intermediate 27 (14.001 g; 0.0432 mol) was added to sodium hydroxide (86ml; 0.086 mol) while stirring. 1,4-Dioxane (175 ml) was added gently tothe stirred reaction mixture. A turbid mixture was formed. The mixturewas heated at 45° C. and the product was dissolved in 30 minutes. Afterheating for 20 hours, the reaction mixture was cooled off in icewaterand HCl 1M (86 ml) was added. The product was filtered off, washed withwater and dried in vacuo at 50° C., yielding 12.16 g of intermediate 28(95%).

c) Preparation of Intermediate 29

POCl₃ (5 ml; 53.642 mmol) was added to intermediate 28 (405.344 mg;1.368 mmol) and 1-phenyl-1H-Pyrazole-4,5-diamine dihydrochloride (338mg; 1.368 mmol). The fine suspension was stirred overnight at 100° C.The reaction mixture was poured unto ice and stirred for an hour. Whilecooling on an ice bath, some DCM was added and made alkaline with 50%NaOH. The resulting salt was filtered off and the DCM layer wasseparated. The aqueous layer was mixed with the salt and extracted twicewith DCM. The combined DCM layers were dried (MgSO₄), filtered andevaporated. The residue was purified by reversed phase high-performanceliquid chromatography (Shandon Hyperprep® C18 BDS (Base DeactivatedSilica) 8 μm, 250 g, I.D. 5 cm). A gradient with 2 mobile phases wasapplied. Phase A: 90% of a 0.5% NH₄OAc solution in water+10% CH₃CN;phase B: CH₃CN). The desired fractions were collected and the eluent wasevaporated. The residue was neutralized with NaHCO₃, extracted with DCMand dried (MgSO₄), filtered and the solvent was evaporated, yielding 254mg of intermediate 29 (43%).

d) Preparation of Intermediate 30

Intermediate 29 (1.279 g; 2.943 mmol) was hydrogenated with Pd/C 10%(0.5 g) in methanol (150 ml) under N₂ atmosphere. The reaction mixturewas stirred at 25° C. under H₂ atmosphere until 1 eq. hydrogen wasabsorbed. The catalyst was filtered off over dicalite and the residuewas evaporated, yielding 959 mg of intermediate 30 (95%).

Example A11 Preparation of Intermediate 31 and Intermediate 32

2,6-Dichloro-4-chloromethyl-phenylamine (11 g, 0.0445 mol) was addedportionwise to a stirring solution of pyrrolidine (15.84 g, 0.223 mol)in CH₃CN (250 ml). The reaction mixture was placed in a water bath(exothermic reaction). The solvent was evaporated and the residue wasdissolved in CH₂Cl₂ (150 ml) and a 50% saturated NaHCO₃ solution (100ml). The mixture was stirred for 15 minutes. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated andco-evaporated with toluene. The oily residue (11.46 g) was stirred inDIPE (30 ml) for 15 minutes and then the DIPE was evaporated again. Theresidue was combined with 2.65 g of another batch and the total amountof crude product was purified by column chromatography over silicagel(eluent: CH₂Cl₂/MeOH 95/5). The pure fractions were combined and thesolvent was evaporated and co-evaporated with toluene. The residue wasstirred in DIPE (25 ml). The DIPE was decanted from the solid, yieldinga DIPE layer (*) and a solid. The remaining DIPE on the solid wasevaporated and the solid was dried (50° C., in vacuo), yielding 2.75 gof intermediate 31 (28.18%). The impure fractions from the column werecombined and the solvent was evaporated and co-evaporated with toluene.The residue (7.45 g) was dissolved in DIPE (20 ml) and 6N HCl in2-propanol (5 ml) was added while the mixture was stirred vigorously. Ayellowish oil was formed that became solid after continuous stirring.The solid was filtered off and washed with DIPE, yielding a filtrate (*)and a solid. The solid was dried (50° C., in vacuo). Yield: 5.19 g ofintermediate 32 (41%; .HCl). The filtrate (*) and the DIPE layer (*)were combined and the solvent was evaporated. The residue (2.59 g) wasdissolved in CH₂Cl₂ and NaHCO₃ in H₂O. The layers were separated and theorganic layer was dried (MgSO₄), filtered and the solvent was partiallyevaporated. The concentrated solution was re-purified over silicagel(eluent: CH₂Cl₂/MeOH 95/5). The pure fractions were collected and thesolvent was evaporated and co-evaporated with toluene. The residue wasdried (50° C., 18 hours, in vacuo). Yield: 1.85 g of intermediate 31(17%).

Example A12 Preparation of Intermediate 33

HCl 1M in Et₂O (10.32 ml; 0.0206 mol) was added to a stirring solutionof intermediate 31 (4.6 g; 0.0188 mol) in CH₃CN p.a. dried on molecularsieves (75 ml) and CH₂Cl₂ p.a (10 ml). Stirring was continued for 1hour. A precipitate was formed. The reaction mixture was cooled on anice-bath, and phosgene 20% in toluene (14 ml) was added. The reactionmixture was stirred further for 3 hours. Extra phosgene 20% in toluene(7 ml) was added, and the reaction mixture was stirred further at roomtemperature for 18 hours. The product was filtered off, washed withCH₃CN (3×) and dried at 50° C. [vacuum, 1 hour], yielding 5.45 g ofintermediate 33 (94%).

Example A13 a) Preparation of Intermediate 34

Hydrazine monohydrate (1.75 g; 35 mmol) was added to 25 ml acetic acid(exothermic). This mixture was added dropwise to intermediate 13 and 50ml of acetic acid at room temperature. The mixture was stirred for 40hours. The solvent was evaporated. The residue was stirred in H₂O,treated with Na₂CO₃ and extracted with CH₂Cl₂. The organic layer wasdried, filtered and evaporated, yielding 5.6 g of intermediate 34.

b) Preparation of Intermediate 35

A mixture of intermediate 34 (0.987 g; 3 mmol) and 15 ml of DMF wasstirred at room temperature. NaH 60% (0.131 g; 3.3 mmol) was added andthe mixture was stirred for 15 minutes at room temperature.1-(Bromomethyl)-4-methoxybenzene (0.475 ml; 3.3 mmol) and 5 ml of DMFwas added dropwise over 15 minutes. The mixture was stirred at roomtemperature for 18 hours. 0.026 g of NaH 60% and 0.095 ml of1-(bromomethyl)-4-methoxybenzene were added and the mixture was stirredfor 3 hours. The solvent was evaporated and the residue was stirred inwater and extracted with CH₂Cl₂. The organic layer was dried, filteredand evaporated. The residue was purified and the regioisomers wereseparated with HPLC method A. The desired fraction was collected and thesolvent was evaporated, yielding 0.699 of intermediate 35.

c) Preparation of Intermediate 36

A mixture of intermediate 35 (0.649 g; 1.4 mmol), 5 ml of HCl/iPrOH and10 ml of CH₃CN was stirred at room temperature for 3 hours. A solidprecipitated and the solvent was evaporated. The residue was dried,yielding 0.748 g of intermediate 36.

Example A14 a) Preparation of Intermediate 38

A mixture of intermediate 11 (0.918 g; 3 mmol), EDCI (0.843 g; 4.4mmol), HOBt (0.594 g; 4.4 mmol) and 10 ml of DMF was stirred at roomtemperature for 15 minutes. Benzenepropanoic acid hydrazide (1.045 g;6.4 mmol) was added. The mixture was stirred at room temperature for 18hours. The solvent was evaporated. The residue was stirred in water andextracted with CH₂Cl₂. The organic layer was dried, filtered andevaporated. The mixture was purified with HPLC method C. The purefraction were collected and the solvent was evaporated. The residue wasdried, yielding 0.941 g of intermediate 38.

b) Preparation of Intermediate 39

A mixture of intermediate 38 (0.863 g; 1.9 mmol) and 15 ml of THF wasstirred at room temperature. 7-Oxa-4-thia-3,5-diazaoctane-2,4-diaminium,3,3-diethyl-6-oxo-, inner salt 4,4-dioxide (0.715 g; 3 mmol) (Burgess'reagent) was added. The mixture was stirred at 60° C. for 3 hours. Thesolvent was evaporated. The residue was stirred in 2 ml of water andextracted with CH₂Cl₂. The mixture was filtered over Isolute filter andthe organic layer was evaporated. The residue was filtered oversilicagel using a mixture of CH₂Cl₂ and CH₃OH (97/3 by volume) aseluent. The pure fraction were collected and the solvent was evaporated.The residue was dried, yielding 0.690 g of intermediate 39.

c) Preparation of Intermediate 40

A mixture of intermediate 39 (0.690 g; 1.59 mmol) and 15 ml of CH₂Cl₂was stirred at room temperature. 1.5 ml of CF₃COOH was added. Themixture was stirred for 3 hours. The solvent was evaporated at 50° C. bya nitrogen stream. The residue was stirred in CH₂Cl₂ and washed withwater and NaHCO₃. The mixture was dried over Isolute filter and theorganic layer was evaporated. The residue was dried, yielding 0.439 g ofintermediate 40.

Example A15 a) Preparation of Intermediate 41

A mixture of N-hydroxybenzenebutanimidamide (0.713 g; 4 mmol), NaH 60%(0.200 g; 5 mmol) and 20 ml of THF was stirred at room temperature.1,1-dimethylethyl 4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylicacid ester (0.640 g; 2 mmol) was added portionwise over 15 minutes. Themixture was stirred and refluxed for 18 hours. The solvent wasevaporated. The residue was stirred in water and extracted with CH₂Cl₂.The organic layer was dried, filtered and evaporated. The residue wasfiltered over silicagel using a mixture of CH₂Cl₂ and CH₃OH (99/1 byvolume) as eluent. The desired fractions were collected and the solventwas evaporated, yielding 0.206 of intermediate 41.

b) Preparation of Intermediate 42

A mixture of intermediate 41 (0.206 g; 0.46 mmol), 4 ml of HCl/iPrOH and8 ml of CH₃CN was stirred at room temperature for 5 hours. The productwas precipitated, filtered off and dried, yielding 0.104 g ofintermediate 42.

Example A16 a) Preparation of Intermediate 43

A mixture of intermediate 11 (0.918 g; 3 mmol), EDCI (0.843 g; 4.4mmol), HOBt (0.594 g; 4.4 mmol) and 10 ml of DMF was stirred at roomtemperature for 15 minutes. Phenylacetic acid hydrazide (1 g; 6.65 mmol)was added. The mixture was stirred at room temperature for 18 hours. Thesolvent was evaporated. The residue was stirred in water and extractedwith CH₂Cl₂. The organic layer was dried, filtered and evaporated. Theresidue was purified by reversed-phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). A gradient with the following mobile phases wasapplied. Phase A: a 0.25% NH₄HCO₃ solution in water; phase B (optional):CH₃OH; phase C: CH₃CN). The desired fractions were collected and thesolvent was evaporated. The residue was dried, yielding 0.802 g ofintermediate 43.

b) Preparation of Intermediate 44

A mixture of intermediate 43 (0.263 g; 0.6 mmol) and 10 ml of THF wasstirred at room temperature. 7-Oxa-4-thia-3,5-diazaoctane-2,4-diaminium,3,3-diethyl-6-oxo-, inner salt 4,4-dioxide (0.214 g; 0.9 mmol) (Burgess'reagent) was added at once. The mixture was stirred at 60° C. for 3hours. The solvent was evaporated. The residue was stirred in 2 ml ofwater and extracted with CH₂Cl₂. The mixture was dried over Isolutefilter and the organic layer was evaporated. The residue was filteredover silicagel using a mixture of CH₂Cl₂ and CH₃OH (96/4 by volume) aseluent. The pure fraction were collected and the solvent was evaporated.The residue was dried, yielding 0.214 g of intermediate 44.

c) Preparation of Intermediate 45

A mixture of intermediate 44 (0.172 g; 0.41 mmol) and 8 ml of CH₂Cl₂ wasstirred at room temperature for 5 minutes. 0.8 ml of CF₃COOH was added.The mixture was stirred at room temperature for 18 hours. The solventwas evaporated at 50° C. by a nitrogen stream. The residue was stirredin water, treated with NaHCO₃ and extracted with CH₂Cl₂. The organiclayer was evaporated and dried, yielding 0.127 g of intermediate 45.

Example A17 a) Preparation of Intermediate 46 and Intermediate 47

A mixture of 1-[4-(1-piperazinyl)phenyl]ethanone (25 g; 0.122 mol),Na₂CO₃ (14.269 g; 0.135 mol) and 150 ml of THF was stirred at roomtemperature. Bromomethyl-benzene (16.102 ml; 0.135 mol) and 50 ml THFwas added dropwise over 30 minutes at room temperature. The mixture wasstirred at room temperature for 18 hours. The solvent was evaporated.The residue was stirred in water and extracted with CH₂Cl₂. The organiclayer was dried, filtered and evaporated. The residue was stirred inDIPE. The product was filtered off and dried, yielding 31.5 g ofintermediate 46.

10 g of intermediate 46 was dissolved in 50 ml acetonitrile. Salt wasformed by adding HBr 48%. The salt was precipitated, filtered off anddried, yielding 5.5 g of intermediate 47.

b) Preparation of Intermediate 48

A mixture of intermediate 47 (3.94 g; 0.00864 mol) and 75 ml ofHBr/CH₃COOH was stirred at room temperature. Br₂ (0.487 ml; 0.0095 mol)was added and the mixture was stirred at room temperature for 18 hours.The mixture was poured in ice water. The product was filtered off,washed with DIPE and dried, yielding 3.69 g of intermediate 48 (80%).

c) Preparation of Intermediate 49

A mixture of intermediate 48 (1.069 g; 0.002 mol), 2-thiazolamine (0.2g; 0.002 mol) and 25 ml of ethanol was stirred at 80° C. for 18 hours.The mixture was cooled. The product was filtered off, washed withethanol and DIPE and dried, yielding 0.794 g of intermediate 49.

d) Preparation of Intermediate 50

Intermediate 49 (0.661 g; 0.00123 mol) was stirred in water, treatedwith Na₂CO₃ and extracted with CH₂Cl₂. The organic layer was dried,filtered and evaporated. The residue and 30 ml of dichloroethane wasstirred at room temperature. 1-Chloroethyl carbonochloridic acid ester(0.161 ml; 0.00148 mol) was added and the mixture was stirred at 85° C.for 2 hours. The solvent was evaporated. The residue was dissolved inmethanol and stirred at 85° C. in a closed vessel for 7 days. Thesolvent was evaporated, yielding 0.357 g of intermediate 50.

Example A18 a) Preparation of Intermediate 51

A mixture 4-(diethylamino)-N-hydroxybutanimidamide (0.693 g; 4 mmol),NaH 60% (0.160 g; 4 mmol) and 20 ml of THF was stirred at roomtemperature. 1,1-Dimethylethyl4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylic acid ester (0.640g; 2 mmol) was added portionwise over 15 minutes. The mixture wasstirred and refluxed for 144 hours. The solvent was evaporated. Theresidue was stirred in water and extracted with CH₂Cl₂. The organiclayer was dried, filtered and evaporated. The residue was purified withHPLC method C. The pure fraction were collected and the solvent wasevaporated. The residue was dried, yielding 0.161 g of intermediate 51.

b) Preparation of Intermediate 52

A mixture of intermediate 51 (0.161 g; 0.36 mmol), 2.5 ml of HCl/iPrOHand 5 ml of CH₃CN was stirred at room temperature for 3 hours. Thesolvent was evaporated, yielding 0.163 of intermediate 52.

Example A19 a) Preparation of Intermediate 53

A mixture of intermediate 48 (2.17 g; 0.004 mol),5-phenyl-2-thiazolamine (2.115 g; 0.012 mol) and 50 ml of ethanol wasstirred at 75° C. for 18 hours. The product was precipitated, filteredoff, washed with DIPE and dried, yielding 1.8 g of intermediate 53.

b) Preparation of Intermediate 54

1-Chloroethyl carbonochloridic acid ester (1.734 ml; 0.0159 mol) wasadded to a stirred mixture of intermediate 53 (1.79 g; 0.00397 mol),1.522 ml of DIPEA and 30 ml of 1,2-dichloroethane. The reaction mixturewas stirred and refluxed for 2 hours. The solvent was evaporated andthree times co-evaporated with xylene, yielding intermediate 54, aresidue used as such in the next reaction.

c) Preparation of Intermediate 55

A mixture of intermediate 54 (1.821 g; 0.0039 mol) and 25 ml of methanolwas refluxed for 18 hours. 2 ml of HBr 48% was added. The reactionmixture was stirred, refluxed for 83 hours and poured into 100 ml H₂Ocontaining 2 g NaHCO₃. After stirring for 15 minutes, the product wasfiltered off, washed with H₂O three times and dried at 50° C. (vacuum),yielding 0.5 g of intermediate 55 (36%).

Example A20 a) Preparation of Intermediate 56

C,C′-bis(1,1-dimethylethyl) dicarbonic acid ester (60.1 g; 0.276 mol)was added in small portions to a stirred solution of1-[4-(1-piperazinyl)phenyl]ethanone (50.0 g; 0.245 mol) in dry CH₂Cl₂(400 ml) at room temperature. The obtained solution was stirred for 0.5hour. The solvent was removed in vacuum. The residue was purified bychromatography (eluent: chloroform), yielding 40.7 g (55%) ofintermediate 56.

b) Preparation of Intermediate 57

Intermediate 56 (78.4 g; 0.258 mol) was dissolved in1,1-dimethoxy-N,N-dimethylmethanamine (300 ml; 2.24 mol) and obtainedsolution was refluxed for 20 hours. Then diisopropyl ether (150 ml) wasadded to the hot solution and obtained mixture was allowed to cool. Theformed crystals were filtered off and washed with diisopropyl ether,yielding intermediate 57.

The filtrate was concentrated in vacuum to remove diisopropyl etherfollowed by reflux of the residue for 10 hours. Then diisopropyl ether(150 ml) was added, the mixture was allowed to cool and the formedcrystals were filtered off to give an additional amount of intermediate57. The total yield of intermediate 57 is 67.5 g (73%).

c) Preparation of Intermediate 58

Hydrazine monohydrate (7.5 ml; 115.0 mmol) was added to a solution ofintermediate 57 (13.8 g; 38.4 mmol) in ethanol (100 ml) and resultingsolution was refluxed for 5 hours. Then water (100 ml) was added to thehot solution, after that ethanol (about 50 ml) was removed bydistillation. The mixture was allowed to cool to room temperature andformed crystals were filtered off, washed with water and dried on air,yielding 11.5 g (91%) of intermediate 58.

d) Preparation of Intermediate 59

Intermediate 58 (15.52 g; 0.0473 mol) was dissolved in dry DMF (100 ml),then NaH 60% (4.16 g; 0.1040 mol) was added and the reaction mixture wasstirred at room temperature for 0.5 hours. Subsequently,2-bromoethylbenzene (14.25 ml; 0.1040 mol) was added and the reactionmixture was stirred for 20 hours more at room temperature. The mixturewas poured out into water (300 ml) and diluted with hexane (100 ml). Theorganic layer was washed with water three times and the organic layerwas separated. The product was filtered off and re-crystallized from themixture DCM-hexane, yielding 15.0 g (73%) of intermediate 59.

e) Preparation of Intermediate 60

Intermediate 59 (23.55 g; 0.0545 mol) was dissolved in dry acetonitrile(500 ml), then HCl 6N (250 ml; 1.50 mol) was added and the reactionmixture was held overnight. After that the reaction mixture wasevaporated to remove acetonitrile (about 400 ml), diluted with water(300 ml) and extracted with benzene. The aqueous layer was separated andbasified with 1N KOH to pH=9-10. This led to the formation of oilyproduct that gradually became crystalline. This product was filtered andwashed with water. Then the precipitate was dissolved in DCM (200 ml)and insoluble admixtures were filtered off. The filtrate wasconcentrated in vacuum, yielding 17.0 g (94%) of intermediate 60.

Example A21 a) Preparation of Intermediate 61

Norite (0.8 g) was added to a solution of methyl4-amino-3,5-dichlorobenzoic acid ester (8.00 g; 36.3 mmol) andtrichloromethyl carbonochloridic acid ester (8.0 ml; 66.2 mmol) in drytoluene (72 ml). The resulting mixture was heated at stirring instainless steel bomb of a Parr apparatus at 110° C. for 20 hours. Thenthe reaction mixture was cooled and filtered through a pad of celite.The filtrate was bubbled with argon for 2 hours to remove phosgene andhydrogen chloride. Then the filtrate was concentrated in vacuum. Thecrude product was treated with cold hexane (15 ml), the precipitate wasfiltered off and the filtrate was evaporated to yield 2.82 g (31.5%) ofintermediate 61. The precipitate was treated with hexane (40 ml) atstirring at 40° C. The small amount of dark sediment was removed byfiltration and the filtrate was concentrated to yield 5.68 g (64%) ofintermediate 61.

The total yield of intermediate 61 is 8.50 g (95%).

B. Preparation of the Compounds Example B1 Preparation of Compound 1

A mixture of intermediate 4 (0.060 g, 0.000161 mol) and1,3-dichloro-2-isocyanatobenzene (0.033 g, 0.000177 mol) in dry THF (1ml) was shaken overnight at room temperature. The solvent was evaporatedand the residue was washed with Et₂O (2×), yielding 0.081 g (90%) ofcompound 1.

Example B2 a) Preparation of Compound 2

A mixture of intermediate 8 (0.085 g, 0.00021 mol), Et₃N (0.091 g,0.0009 mol) and CH₂Cl₂ (5 ml) was stirred for 15 minutes at roomtemperature. 1,3-Dichloro-2-isocyanatobenzene (0.056 g, 0.0003 mol) wasadded and the reaction mixture was stirred overnight at roomtemperature. The mixture was washed with H₂O (2 ml) and was dried overan Isolute filter. The organic layer was evaporated. The residue waspurified by HPLC Method B. The pure fractions were collected and thesolvent was evaporated. The residue was stirred in DIPE. The solvent wasevaporated (stream of N₂ at 50° C.) and the solid was dried, yielding0.046 g of compound 2.

b) Preparation of Compound 3

A mixture of intermediate 10 (0.307 g, 0.00075 mol), Et₃N (0.243 g,0.0024 mol) and CH₂Cl₂ (q.s.) was stirred for 30 minutes at roomtemperature. Subsequently, 1,3-dichloro-2-isocyanatobenzene (0.147 g,0.00078 mol) was added and the reaction mixture was stirred overnight atroom temperature. The mixture was washed with H₂O (2 ml), dried over anIsolute filter and the solvent was evaporated. The residue was stirredin CH₃CN. The product was filtered off, washed with DIPE and dried,yielding 0.21 g of compound 3.

c) Preparation of Compound 4

A mixture of intermediate 15 (0.179 g, 0.0005 mol), Et₃N (0.182 g,0.0018 mol) and CH₂Cl₂ (10 ml) was stirred for 30 minutes at roomtemperature. 1,3-Dichloro-2-isocyanatobenzene (0.112 g, 0.0006 mol) wasadded and the reaction mixture was stirred for 3 hours at roomtemperature. The mixture was washed with H₂O (2 ml) and was dried overan Isolute filter. The organic layer was evaporated and the residue waspurified by high-performance liquid chromatography. The pure fractionswere collected and the solvent was evaporated. The residue wassolidified by stirring in DIPE (2 ml). The solvent was evaporated andthe solid residue was dried, yielding 0.071 g of compound 4.

Example B3 Preparation of Compound 5

Intermediate 17 was converted into its hydrochloric acid salt byliterature-known methods (0.25 g, 0.00049 mol; .HCl), and was then mixedwith 1,3-dichloro-2-isocyanatobenzene (0.102 g, 0.00054 mol) and DIPEA(0.097 g, 0.00075 mol) in CH₂Cl₂ (25 ml) and stirred for 2 hours at roomtemperature. The solvent was evaporated and the residue was crystallizedfrom DIPE. The precipitate was filtered off and dried. The crude productwas stirred in H₂O and the aqueous layer was extracted with CH₂Cl₂. Theseparated organic layer was dried (Extrelut) and the solvent wasevaporated, yielding 0.07 g of compound 5.

Example B4 a) Preparation of Compound 6

A mixture of intermediate 19 (0.00060 mol) and1,3-dichloro-2-isocyanatobenzene (0.00066 mol) in CH₂Cl₂ (20 ml) wasstirred at room temperature for 4 hours. The solvent was evaporated. Theresidue was triturated under DIPE. The precipitate was filtered off anddried, yielding 0.264 g of compound 6.

b) Preparation of Compound 7

1,3-Dichloro-2-isocyanatobenzene (0.000698 mol) was added to a slightlycloudy solution of intermediate 22 (0.000698 mol) in CH₂Cl₂ (10 ml,p.a.), stirred at room temperature. The reaction mixture was stirredovernight at room temperature. The mixture was purified by flash columnchromatography over a Biotage 60 cartridge (eluent: CH₂Cl₂/(7NNH₃/CH₃OH) from 100/0 to 95/5 v/v). The product fractions were collectedand the solvent was evaporated, yielding 0.171 g of compound 7.

Example B5 Preparation of Compound 8

A mixture of intermediate 25 (0.060 g, 0.000193 mol),2,6-dichlorobenzeneacetic acid (0.048 g, 0.000232 mol), EDCI (0.044 g,0.000232 mol), HOBt.H₂O (0.036 g, 0.000232 mol) and DIPEA (0.000965 mol)in dry CH₂Cl₂ (1 ml) was shaken overnight at 50° C. CH₂Cl₂ was added tothe mixture and the mixture was extracted with NaHCO₃ (half saturated)and H₂O. The separated organic layer was filtered over silica and dried(MgSO₄). The solvent was evaporated. The residue was purified bypreparative HPLC (column100×21 mm, Nucleosil (Macherey-Nagel) Si50, 10μm; gradient: CH₂Cl₂/CH₃OH: 0.0 min: 100/0; 1.2 min: 100/0; 5.0 min:0/100; 9.0 min. 0/100; flow rate: 35 ml/min). The desired fractions werecollected and worked-up, yielding 0.070 g (73%) of compound 8.

Example B6 Preparation of Compound 24

A mixture of intermediate 26 (0.250 g, 0.00058 mol),1,3-dichloro-2-isocyanatobenzene (0.121 g, 0.00064 mol) and CH₂Cl₂ (25ml) was stirred for 2 hours at room temperature. The solvent wasevaporated and DIPE was added to the residue. The solid was filtered offand dried. The crude compound was purified by reversed-phase HPLC (HPLCmethod C). The desired fractions were collected and worked-up, yielding0.204 g of compound 24.

Example B7 Preparation of Compound 29

A mixture of intermediate 36 (0.295 g; 0.7 mmol), triethylamine (0.56ml; 4 mmol) and CH₂Cl₂ (10 ml) was stirred at room temperature for 15minutes. 1,3-Dichloro-2-isocyanatobenzene (0.188 g; 1 mmol) was added.The mixture was stirred at room temperature for 18 hours. The mixturewas washed with 2 ml water and dried over Isolute filter. The organiclayer was evaporated. The residue was filtered over silica gel using amixture of CH₂Cl₂ and CH₃OH (97/3 by volume) as eluent. The purefractions were collected and the solvent was evaporated. The residue wasdried, yielding 0.277 g of compound 29.

Example B8 Preparation of Compound 54

To a suspension of intermediate 32 (527.048 mg; 1.872 mmol) in 10 ml ofacetonitrile and 4 ml of DCM, C(═O)Cl₂ 20% in toluene (1.701 ml; 3.403mmol) was added. The suspension was stirred overnight at roomtemperature. The reaction was filtered and washed with fresh dry CH₃CN.The isocyanate precipitate was added to a suspension of intermediate 30(586 mg; 1.701 mmol) and DIPEA (0.845 ml; 5.104 mmol in DCM (20 ml).Meanwhile, the filtrate was concentrated at 30° C. to remove DCM and 1.7ml of fresh C(═O)Cl₂ 20% in toluene was added and stirred for 3 hours atroom temperature. A second batch of intermediate 32 (431 mg) was addedto the mixture and stirred overnight. The suspension was filtered, theresidue was washed with a little dry CH₃CN and added to the reactionmixture of intermediate 30. The reaction was evaporated. The residue waspurified by reversed phase high-performance liquid chromatography(Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with the following mobile phases was applied. Phase A:90% of a 0.5% NH₄OAc solution in water+10% CH₃CN; phase B (optional):CH₃OH; phase C: CH₃CN). The desired fractions were collected, partiallyevaporated at 30° C. and neutralized to pH 8-9 with a saturated NaHCO₃solution. The formed precipitate was filtered off and dried, yielding820 mg of compound 54 (78%).

Table 1a lists compounds of formula (I) according to the presentinvention prepared by analogy to one of the above Example Nr.

TABLE 1a

Co. Ex. No. No. A X R¹ R^(q)  1 B1 N

H—  2 B2.a N

H—  3 B2.b N

H—  4 B2.c N

H—  5 B3 N

H—  6 B4.a N

H—  7 B4.b CH

H—  8 B5 N

H—  9 B1 N

H— 10 B2.a N

H— 11 B2.a N

H— 12 B2.a N

H— 13 B2.a N

H— 14 B2.a N

H— 15 B2.a N

H— 16 B2.a N

H— 17 B2.a N

H— 18 B2.a N

H— 19 B2.b N

H— 20 B2.b N

H— 21 B2.b N

H— 22 B2.c N

H— 23 B2.c N

H— 24 B6 N

H— 25 B4.a N

H— 26 B4.a N

H— 27 B5 N

H— 28 B7 N

H— 29 B7 N

H— 30 B7 N

H— 31 B7 N

H— 32 B7 N

H— 33 B7 N

H— 34 B7 N

H— 35 B7 N

H— 36 B7 N

H— 37 B7 N

H— 38 B7 N

H— 39 B7 N

H— 40 B7 N

H— 41 B2.a N

H— 42 B7 N

H— 43 B7 N

H— 44 B4.b CH

H— 45 B2.c N

H— 46 B4.b CH

H— 47 B2.c N

H— 48 B4.b CH

H— 49 B7 N

H— 50 B4.b CH

H— 51 B7 N

H— 52 B5 N

H— 53 B8 N

54 B8 N

55 B8 N

56 B8 N

57 B2.a N

HOCH₂— 58 B8 N

59 B2.a N

HOCH₂— 60 B8 N

61 B2.a N

HO— 62 B2.a N

HO— 63 B7 N

64 B8 N

65 B7 N

TABLE 1b

Co. No. X R¹ R² Salt  66

 67

 68

 69

 70

 71*

 72

 73*

 74*

 75

 76*

 77

 78

 79

 80*

 81

 82

 83

 84

 85

 86

 87*

 88

 89

 90

 91

 92

 93*

 94

 95

 96

 97

 98*

 99

100

101

102

103

104

105

106

107*

108

109*

110

111*

112

113*

114

115

trifluoroacetate salt 116

117*

*library compounds from third party

C. Analytical Part

LCMS

For LCMS-characterization of the compounds of the present invention, thefollowing methods were used.

General Procedure A

The HPLC measurement was performed using an Alliance HT 2790 (Waters)system comprising a quaternary pump with degasser, an autosampler, acolumn oven (set at 40° C., unless otherwise indicated), a diode-arraydetector (DAD) and a column as specified in the respective methodsbelow. Flow from the column was split to a MS detector. The MS detectorwas configured with an electrospray ionization source. Mass spectra wereacquired by scanning from 100 to 1000 in 1 second using a dwell time of0.1 second. The capillary needle voltage was 3 kV and the sourcetemperature was maintained at 140° C. Nitrogen was used as the nebulizergas. Data acquisition was performed with a Waters-MicromassMassLynx-Openlynx data system.

General Procedure B

The LC measurement was performed using an Acquity UPLC (Waters) systemcomprising a binary pump, a sample organizer, a column heater (set at55° C.), a diode-array detector (DAD) and a column as specified in therespective methods below. Flow from the column was split to a MSdetector. The MS detector was configured with an electrospray ionizationsource. Mass spectra were acquired by scanning from 100 to 1000 in 0.18seconds using a dwell time of 0.02 seconds. The capillary needle voltagewas 3.5 kV and the source temperature was maintained at 140° C. Nitrogenwas used as the nebulizer gas. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system.

General Procedure C

The LCMS analyses for the compounds were done at the Surveyor MSQ™(Thermo Finnigan, USA) comprising a photo diode array detector (PDA;190-800 nm) and a column as specified in the respective methods below.Flow from the column was split to a MS spectrometer. The MS detector wasconfigured with APCI (atmospheric pressure chemical ionization, + or −ions). Mass spectra were acquired by scanning from 45 to 1000 (of atomicmass unit) in 0.3 seconds. Typical APCI conditions use a coronadischarge current of 10 μA and a cone voltage of 30 V. The APCI probetemperature was 640° C. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with an Xcalibur™ data system.

LCMS Procedure 1

In addition to general procedure A: Reversed phase HPLC was carried outon an Xterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of 1.6ml/min. Three mobile phases (mobile phase A: 95% 25 mMammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobilephase C: methanol) were employed to run a gradient condition from 100% Ato 1% A, 49% B and 50% C in 6.5 minutes, to 1% A and 99% B in 1 minuteand hold these conditions for 1 minute and reequilibrate with 100% A for1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10V for positive ionization mode and 20 V for negative ionization mode.

LCMS Procedure 2

In addition to general procedure A: Column heater was set at 60° C.Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm,4.6×100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobilephase A: 95% 25 mM ammoniumacetate+5% acetonitrile; mobile phase B:acetonitrile; mobile phase C: methanol) were employed to run a gradientcondition from 100% A to 50% B and 50% C in 6.5 minutes, to 100% B in0.5 minute and hold these conditions for 1 minute and reequilibrate with100% A for 1.5 minutes. An injection volume of 10 μl was used. Conevoltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

LCMS Procedure 3

In addition to general procedure A: Reversed phase HPLC was carried outon a Chromolith (4.6×25 mm) with a flow rate of 3 ml/min. Three mobilephases (mobile phase A: 95% 25 mM ammoniumacetate+5% acetonitrile;mobile phase B: acetonitrile; mobile phase C: methanol) were employed torun a gradient condition from 96% A, 2% B and 2% C, to 49% B and 49% Cin 0.9 minutes, to 100% B in 0.3 minutes and hold for 0.2 minutes. Aninjection volume of 2 μl was used. Cone voltage was 10 V for positiveionization mode and 20 V for negative ionization mode.

LCMS Procedure 4

In addition to general procedure B: Reversed phase UPLC (UltraPerformance Liquid Chromatography) was carried out on a bridgedethylsiloxane/silica (BEH) C18 column (1.7 μm, 2.1×50 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1% formic acidin H₂O/methanol 95/5; mobile phase B: methanol) were used to run agradient condition from 95% A and 5% B to 5% A and 95% B in 1.3 minutesand hold for 0.2 minutes. An injection volume of 0.5 μl was used. Conevoltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

LCMS Procedure 5

In addition to general procedure C: Reversed phase HPLC was carried outon a Waters XTerra MS C18 column (3.5 μm, 2.1×30 mm) with a flow rate of1.0 ml/min. Two mobile phases (mobile phase A: 0.1% aqueous solution offormic acid; mobile phase B: acetonitrile) were used. First, 100% A washold for 0.1 minutes. Then a gradient was applied to 5% A and 95% B in 3minutes and hold for 0.8 minutes. The injection volume was 1 μl. Thecolumn was at room temperature.

Melting Points

For a number of compounds, melting points were determined with a DSC823e(Mettler-Toledo). Melting points were measured with a temperaturegradient of 30° C./minute. Maximum temperature was 400° C.

Values are peak values and are obtained with experimental uncertaintiesthat are commonly associated with this analytical method.

For a number of compounds, melting points were determined by using aGallenkamp apparatus from Sanyo Gallenkamp. The melting pointsdetermined in this way are indicated with ‘*’.

TABLE 2a LCMS and melting point analytical data (R_(t): Retention timein minutes; [M + H]+ means the protonated mass of the compound, LCMSprocedure refers to the method used for LCMS). Comp. LCMS Nr. R_(t) [M +H]⁺ Procedure Melting point (° C.) 1 1.28 560 4 n.d. 9 1.15 498 4 n.d. 81.26 497 4 n.d. 27 1.36 559 4 n.d. 2 6.23 520 1 163.4 6 5.81 537 1 207.910 6.10 506 1 191.4 24 5.96 615 1 n.d. 4 5.36 473 2 135.5 5 6.23 657 1n.d. 25 0.89 489 3 165.7 3 5.96 525 2 203.2 22 5.33 507 2 209.4 19 5.89513 2 179.3 23 5.46 521 2 181.0 26 5.15 475 1 194.1 20 5.57 533 2 220.37 4.98 474 2 215.0 11 5.99 586 2 249.8 12 5.96 498 2 n.d. 14 6.60 504 1222.3 13 6.22 520 1 167.3 15 5.44 472 2 183.2 21 6.04 511 2 247.7 166.61 484 1 193.8 17 5.43 598 2 n.d. 18 5.27 522 2 n.d. 28 5.67 521 1174.8 29 5.24 537 2 185.4 30 5.97 535 1 181.9 31 5.70 522 2 189.4 325.26 473 2 175.2 33 6.59 536 1 146.3 34 6.18 508 1 180.1 35 5.44 508 2201.0 36 5.52 474 2 181.9 38 5.75 474 1 214.0 39 6.28 474 1 209.3 404.94 459 2 186.7 41 6.04 534 2 137.3 42 4.34 418 1 n.d. 43 n.d. n.d. —n.d. 44 1.94 550 5 177-178* 45 5.17 537 2 173.9 46 1.85 552 5 100-105*47 4.89 459 2 202.5 48 1.89 536 5 200-201* 49 4.87 432 1 235.0 50 1.85522 5 180-181* 51 4.39 531 2 n.d. 52 6.83 547 1 290.5 53 5.26 507 2 n.d.54 5.78 615 1 231.7 55 5.32 643 2 208.4 56 5.09 629 2 160.2 57 1.83 5505 147-148* 58 4.77 581 2 n.d. 59 1.91 564 5 189-191* 60 n.d. n.d. —172.8 61 1.85 536 5 165-167* 62 1.95 550 5 207-209* 63 2.01 578 5194-195* 64 n.d. n.d. — 235.3 65 2.07 592 5 148-149* 66 1.19 498 4 n.d.67 1.19 464 4 n.d. 68 1.31 560 4 n.d. 69 1.30 498 4 n.d. 70 1.32 526 4n.d. 71 1.51 474 4 n.d. 72 1.20 480 4 n.d. 73 1.48 500 4 n.d. 74 1.37438 4 n.d. 75 1.40 560 4 n.d. 76 1.49 466 4 n.d. 77 1.32 542 4 n.d. 780.88 473 4 n.d. 79 1.06 535 4 n.d. 80 1.41 482 4 n.d. 81 1.19 444 4 n.d.82 1.11 460 4 n.d. 83 1.30 522 4 n.d. 84 1.17 460 4 n.d. 85 1.20 444 4n.d. 86 1.21 476 4 n.d. 87 1.25 415 4 n.d. 88 1.26 480 4 n.d. 89 1.14444 4 n.d. 90 1.14 460 4 n.d. 91 1.13 515 4 n.d. 92 1.11 474 4 n.d. 931.32 429 4 n.d. 94 1.26 522 4 n.d. 95 1.27 492 4 n.d. 96 1.18 456 4 n.d.97 1.16 549 4 n.d. 98 1.25 442 4 n.d. 99 1.25 536 4 n.d. 101 1.14 430 4n.d. 102 1.28 506 4 n.d. 103 1.26 577 4 n.d. 104 1.16 429 4 n.d. 1051.32 506 4 n.d. 106 0.99 473 4 n.d. 107 1.34 441 4 n.d. 108 1.30 491 4n.d. 109 1.45 492 4 n.d. 110 1.34 505 4 n.d. 111 1.29 441 4 n.d. 1121.24 464 4 n.d. 113 1.44 481 4 n.d. 115 1.07 474 4 n.d. 116 1.35 526 4n.d. 117 1.38 467 4 n.d. n.d. = not determined

TABLE 2b LCMS analytical data - R_(t) means retention time (in minutes),[M − H]⁻ means the deprotonated mass of the compound (negative mode),LCMS procedure refers to the method used for LCMS. Comp. LCMS MeltingNr. R_(t) [M − H]⁻ procedure point (° C.) 37 6.46 492 1 232.4

D. Pharmacological Example A) Measurement of Inhibition of DGAT1Activity by the Present Compounds

The inhibiting activity of the present compounds on DGAT1 activity wasscreened in a single well procedure assay using DGAT1 comprisingmembrane preparations and DGAT1 substrate comprising micelles anddetermining formed radio-active triacylglycerol coming in closeproximity of a flashplate surface by radioluminescence.

Said assay is described in full detail in WO2006/067071, the content ofwhich is incorporated herein by reference.

By DGAT1 activity is meant the transfer of coenzyme A activated fattyacids to the 3-position of 1,2-diacylglycerols, thus forming atriglyceride molecule, by enzyme DGAT1.

Step 1 of the Assay: Expression of DGAT1

human DGAT1 (NM012079.2) was cloned into the pFastBac vector, containingtranslation start, a FLAG-tag at the N-terminus as described inliterature and a viral Kozak sequence (AAX) preceding the ATG to improveexpression in insect cells. Expression was done as described inliterature (Cases, S., Smith, S. J., Zheng, Y., Myers H. M., Lear, S.R., Sande, E., Novak, S., Collins, C., Welch, C. B., Lusis, A. J.,Erickson, S. K. and Farese, R. V. (1998) Proc. Natl. Acad. Sci. USA 95,13018-13023.) using SF9 cells.

Step 2 of the Assay: Preparation of DGAT1 Membranes

72 h transfected SF9 cells were collected by centrifugation (13000rpm-15 min-4° C.) and lysed in 2× 500 ml lysisbuffer (0.1M Sucrose, 50mM KCl, 40 mM KH₂PO₄, 30 mM EDTA pH 7.2. Cells were homogenized by celldisruptor. After centrifugation 1380 rpm-15 min-4° C. (SN discarded),pellet was resuspended in 500 ml lysisbuffer and total cell membranescollected by ultracentrifugation at 34000 rpm (100 000 g) for 60 min (4°C.). The collected membranes were resuspended in lysis buffer, dividedin aliquots and stored with 10% glycerol at −80° C. until use.

Step 3 of the Assay: Preparation of DGAT Substrate Comprising Micelles

Materials

-   a) 1,2-dioleoyl-sn-glycerol, 10 mg/ml (1,2-diacylglycerol (DAG))    -   Dissolve in acetonitrile; evaporate the acetonitrile solution        under nitrogen and reconstitute in chloroform at a final        concentration of 10 mg/ml.-   b) L-α-phosphatidylcholine, 1 mg/ml (phosphatidylcholine (PC))    -   Dissolve in chloroform at a final concentration of 1 mg/ml and        store at 4° C.-   c) L-α-phosphatidyl-L-serine, 1 mg/ml (phophatidylserine (PS))    -   Dissolve in chloroform at a final concentration of 1 mg/ml and        store at 4° C.        Method

Add 1 ml dioleoyl-sn-glycerol (10 mg/ml) to 10 ml ofL-α-phosphatidylcholine (1 mg/ml) and 10 ml of L-α-phosphatidyl-L-serine(1 mg/ml) in a thick glass recipient. Evaporate under nitrogen and puton ice for 15 minutes. Reconstitute in 10 ml Tris/HCl (10 mM, pH 7.4) bysonication on ice. The sonification process consists of sonificationcycles of 10 seconds in the sonification bath followed by 10 secondscool down on ice and repeating this sonification cycle till ahomogeneous solution is obtained (takes about 15 minutes). The thusobtained micelles are stored at −20° C. till later use and contain DAGat a final concentration of 1.61 mM.

Step 4 of the Assay: DGAT FlashPlate™ Assay

Materials

-   a) Assaybuffer    -   50 mM Tris-HCl (pH 7.4), 150 mM MgCl₂, 1 mM EDTA, 0.2% BSA.-   b) N-ethylmaleimide, 5M    -   Dissolve 5 g into a final volume of 8 ml DMSO 100% and store at        −20° C. in aliquots till later use.-   c) Substrate mix (for 1 384 well plate=3840 μl)    -   612 μl micelles stock (51 μM final)    -   16.6 μl oleoylCoA 9.7 mM    -   23 μl [³H]-oleoylCoA (49 Ci/mmol, 500 μCi/ml)    -   3188.4 μl Tris pH 7.4, 10 mM-   d) Enzyme mix (for 1 384 well plate=3520 μl) (5 μg/ml)    -   Add 11.73 μl of DGAT membrane stock (1500 μg/ml stock) to 3508        μl assay buffer.-   e) Stop mix (for 1 384 well plate=7.68 ml) (250 mM)    -   Add 384 μl of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and        further dilute 3.84 ml of said solution with 3.84 ml DMSO 10%.        Method

DGAT activity in membrane preparations was assayed in 50 mM Tris-HCl (pH7.4), 150 mM MgCl₂, 1 mM EDTA and 0.2% BSA, containing 50 μM DAG, 32μg/ml PC/PS and 8.4 μM [³H]-oleoylCoA (at a specific activity of 30nCi/well) in a final volume of 50 μl in 384-well format using the redshifted Basic Image FlashPlate™ (Perkin Elmer Cat.No. SMP400).

In detail, 10 μl enzyme mix and 10 μl substrate mix were added to 30 μlof assay buffer, optionally in the presence of 1 μl DMSO (blank andcontrols) or 1 μl of the compound to be tested. This reaction mixturewas incubated for 120 minutes at 37° C. and the enzymatic reactionstopped by adding 20 μl of the stop mix. The plates were sealed and thevesicles allowed to settle overnight at room temperature. Plates werecentrifuged for 5 minutes at 1500 rpm and measured in Leadseeker.

Experiments with different concentrations of the test compound wereperformed and curves were calculated and drawn based on % CTRL_(min) (%of normalized control). % CTRL_(min) was calculated according toequation 1,% CTRL_(min)=(sample−LC)/(HC−LC)  Equation 1where HC (high control) refers to the median of radioluminescence valuemeasured in the wells with enzyme and substrate but without testcompound, LC (low control) refers to median background radioluminescencevalue measured in the wells with substrate without enzyme and withouttest compound, and sample refers to the radioluminescence value measuredin the wells with substrate, enzyme and test compound at a particularconcentration.

The calculated % CTRL_(min), values form a sigmoidal dose responsedescending curve and from this curve pIC₅₀ values were calculated (−logIC₅₀ where IC₅₀ represents the concentration at which the test compoundgives 50% inhibition of DGAT1 activity). Table 3 shows the pIC₅₀ valuesfor the compounds of formula (I).

In order to determine selectivity of the present compounds for DGAT1compared to DGAT2, the inhibiting activity of the compounds on DGAT2 wasalso determined in the above assay, slightly modified to obtain optimalassay conditions for DGAT2. The tested compounds did not show inhibitingactivity for DGAT2 (Human DGAT2 (NM032564) was cloned and expressed asdescribed in J. Biolog. Chem. 276(42), pp 38870-38876 (2001)).

TABLE 3 pIC₅₀ values (IC₅₀ values expressed in M) Co. pIC₅₀ (mean iftested Co. pIC₅₀ (mean if tested No. more than once) No. more than once)7 5.61 103 5.38 26 5.74 79 5.74 25 6.13 99 5.42 6 6.52 108 5.31 20 5.8895 5.45 3 6.30 105 5.36 19 5.99 94 5.45 21 5.24 116 5.04 17 5.17 83 5.5111 5.71 97 5.44 16 5.19 96 5.45 14 5.46 102 5.39 12 5.55 110 5.14 155.31 77 5.86 18 5.05 68 6.89 10 6.50 75 5.94 13 5.46 49 5.73 2 6.96 336.98 23 5.93 44 6.03 22 6.00 48 5.76 4 6.39 46 5.93 9 8.19 50 5.71 87.52 39 6.40 1 8.05 37 6.76 27 6.92 28 7.60 24 6.35 38 6.56 5 6.18 515.52 45 6.03 35 6.84 29 7.51 34 6.85 42 6.13 63 6.12 47 5.77 57 7.63 307.49 65 5.81 41 6.22 59 7.13 32 7.08 36 6.82 40 6.39 61 6.82 115 5.05 626.47 70 6.74 31 7.39 58 7.33 67 7.07 56 7.76 112 5.10 53 7.91 66 7.10 607.01 90 5.47 55 7.82 85 5.50 64 5.92 92 5.47 43 6.12 89 5.47 93 5.46 785.79 74 6.02 84 5.50 117 5.04 82 5.54 107 5.32 81 5.58 80 5.69 86 5.48113 5.09 91 5.47 76 5.87 106 5.33 73 6.04 88 5.48 109 5.27 72 6.08 716.10 101 5.39 98 5.43 69 6.78 111 5.12 100 5.40 87 5.48 104 5.37 54 7.8852 n.d. 114 5.07

B) In Vivo Study for Effect of Test Compound on GLP-1 Plasma Levels

Elevation of GLP-1 plasma levels by a DGAT inhibitor can be studied asfollows:

Dogs are deprived from food for a period of 22 hours. At time 0, animalsare given a liquid meal, containing 18% fat (w/w), by gavage with astomach tube. The test compound is given orally together with the meal.Afterwards, a postprandial plasma profile is determined for GLP-1.Therefore, blood is collected at predetermined time intervals inice-cooled Vacutainers EDTA-plasma tubes and GLP-1 levels are measuredin the samples taken at 0 hour (just before the meal) and at 0.5, 1, 2,4, 6, 8 and 24 hours after dosing. Six dogs (3 males and 3 females) areincluded per dosage group and the plasma GLP-1 profile is compared withtheir own GLP-1 profile previously determined in the same conditions butwithout administration of the test compound.

GLP-1 determinations in plasma are performed with a Glucagon-likepeptide-1 (active) ELISA kit 96-well plate of LINCO Research.

E. Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa compound of formula (I), including any stereochemically isomeric formthereof, a N-oxide thereof, a pharmaceutically acceptable salt thereofor a solvate thereof; in particular to any one of the exemplifiedcompounds.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

The invention claimed is:
 1. A compound of formula

including any stereochemically isomeric form thereof, wherein Arepresents N; X represents —NR^(x)—C(═O)—; —Z—C(═O)—; or—Z—NR^(x)—C(═O)—; Z represents a bivalent radical selected fromC₁₋₆alkanediyl, R^(x) represents hydrogen; R¹ represents a 5-memberedmonocyclic heterocycle selected from the group consisting of1,3-dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl,thiadiazolyl, oxadiazolyl, tetrazolyl; wherein each of said heterocyclesmay optionally be substituted with one or two substituents, eachsubstituent independently being selected from the group consisting ofC₁₋₆alkyl optionally substituted with C₁₋₄alkyl oxycarbonyl;hydroxyC₁₋₆alkyl optionally substituted with aryl; mono- ordi(C₁₋₆alkyl)-amino; R⁵R⁴N—C₁₋₆alkyl; Het-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cyclo-alkylC₁₋₄alkyl; aryl;arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; and Het; R² represents R³; R³represents C₃₋₆cycloalkyl, phenyl, naphthalenyl, 1,3-benzodioxolyl, or a6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein saidC₃₋₆cycloalkyl, phenyl, naphthalenyl, 1,3-benzodioxolyl or 6-memberedaromatic heterocycle may optionally be substituted with at least onesubstituent, each substituent independently selected from the groupconsisting of hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substitutedwith hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkyloxycarbonyl; mono- or di(C₁₋₄alkyl)amino;C₁₋₄alkylcarbonylamino Het; and HetC₁₋₄alkyl; R⁴ represents hydrogen; orC₁₋₄alkyl; R⁵ represents hydrogen or C₁₋₄alkyl; R⁸ represents hydrogen;aryl represents phenyl or phenyl substituted with at least onesubstituent, each substituent independently being selected from thegroup consisting of halo; C₁₋₆alkyl and C₁₋₆alkyloxy; Het representspiperidinyl, morpholinyl, piperazinyl or pyrrolidinyl; said piperidinyl,morpholinyl, piperazinyl or pyrrolidinyl, optionally being substitutedwith C1-6alkyloxycarbonyl; p represents 1 or 2; provided that thefollowing compounds

X R¹ R²

are excluded; a N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 2. The compound as claimed in claim 1having the following formula

including any stereochemically isomeric form thereof, wherein Arepresents N; X represents —NR^(x)—C(═O)—; —Z—C(═O)—; or—Z—NR^(x)—C(═O)—; Z represents a bivalent radical selected fromC₁₋₆alkanediyl; R¹ represents a 5-membered monocyclic heterocycleselected from the group consisting of 1,3-dioxolanyl, imidazolidinyl,thiazolidinyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl,oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl,imidazolinyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl,tetrazolyl; wherein each of said heterocycles may optionally besubstituted with one or two substituents, each substituent independentlybeing selected from the group consisting of hydroxyC₁₋₆alkyl optionallysubstituted with aryl; and Het; R² represents R³; R³ representsC₃₋₆cycloalkyl, phenyl, naphthalenyl, 1,3-benzodioxolyl, wherein saidC₃₋₆cycloalkyl, phenyl, naphthalenyl, 1,3-benzodioxolyl may optionallybe substituted with at least one substituent, each substituentindependently selected from the group consisting of hydroxyl; carboxyl;halo; C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; mono- ordi(C₁₋₄alkyl)amino; aryl represents phenyl or phenyl substituted with atleast one substituent, each substituent independently being selectedfrom the group consisting of halo; C₁₋₆alkyl and C₁₋₆ alkyloxy; Hetrepresents piperidinyl, morpholinyl, piperazinyl or pyrrolidinyl; saidpiperidinyl, morpholinyl, piperazinyl or pyrrolidinyl, optionally beingsubstituted with C1-6alkyloxycarbonyl; p represents 1 or 2; a N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 3. The compound as claimed in claim 1 wherein the compound hasthe following formula

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆ alkyl optionally substituted withhydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;C₁₋₆alkyloxycarbonyl; mono- or di(C₁₋₄alkyl)amino; orC₁₋₄alkylcarbonylamino; and wherein R^(3c) represents hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; mono- or di(C₁₋₄alkyl)amino; Het;or HetC₁₋₄alkyl.
 4. The compound as claimed in claim 1 wherein thecompound has the following formula

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆ alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl, or mono- or di(C₁₋₄alkyl)amino; andwherein R^(3c) represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyloptionally substituted with hydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; mono- or di(C₁₋₄ alkyl)amino;C₁₋₄alkylcarbonylamino; Het; or HetC₁₋₄alkyl.
 5. The compound as claimedin claim 3 wherein R^(3a) and R^(3b) each independently represent haloor C₁₋₆alkyl.
 6. The compound as claimed in claim 3 wherein both R^(3a)and R^(3b) represent halo.
 7. The compound as claimed in claim 3 whereinR^(3c) represents HetC₁₋₄alkyl.
 8. The compound as claimed in claim 1wherein the compound is selected from

A X R¹ R^(q) N

H— N

HOCH₂—

a N-oxide thereof, or a pharmaceutically acceptable salt thereof or asolvate thereof.
 9. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and as active ingredient atherapeutically effective amount of a compound as claimed in claim 1.